Imidazopyridine derivatives as melancortin receptor agonists

ABSTRACT

Derivatives of imidazopyridine which have a good affinity for certain sub-types of melanocortin receptors, in particular MC4 receptors and are useful for treating pathological states and diseases in which one or more melanocortin receptors are involved and pharmaceutical compositions containing said products.

This application is a 371 of PCT FR2004/000785 filed Mar. 29, 2004.

A subject of the present application is novel imidazo-pyridinederivatives. These products have a good affinity for certain sub-typesof melanocortin receptors, in particular MC4 receptors. They areparticularly useful for treating the pathological states and diseases inwhich one or more melanocortin receptors are involved. The inventionalso relates to pharmaceutical compositions containing said products andtheir use for the preparation of a medicament.

The melanocortins represent a group of peptides which derive from thesame precursor, proopiomelanocortin (POMC), and which are structurallyclose: adrenocorticotropic hormone (ACTH), α-melanocyte-stimulatinghormone (α-MSH), β-MSH and γ-MSH (Eipper B. A. and Mains R. E., Endocr.Rev. 1980, 1, 1-27). The melanocortins perform numerous physiologicalfunctions. They stimulate the synthesis of steroids by the adrenalcortex and the synthesis of eumelanin by the melanocytes. They regulatefood intake, energy metabolism, sexual function, neuronal regeneration,blood pressure and heart rate, as well as the perception of pain,learning, attention and memory. The melanocortins also possessanti-inflammatory and anti-pyretic properties and control the secretionof several endocrine or exocrine glands such as the sebaceous, lacrymal,mammary glands, the prostate and the pancreas (Wikberg J. E. et al.Pharmacol. Res. 2000, 42, 393-420; Abdel-Malek Z. A., Cell. Mol. Life.Sci. 2001, 58, 434-441).

The effects of the melanocortins are mediated by a family of membranereceptors specific to seven transmembrane domains and coupled to the Gproteins. Five sub-types of receptors, named MC1 to MC5, have beencloned and characterized to date. These receptors differ in their tissuedistribution and by the affinity of the different melanocortins, the MC2receptors only recognizing ACTH. The stimulation of the melanocortinreceptors activates adenylate cyclase with production of cyclic AMP. Ifthe specific functional roles of each of the receptors are not totallyexplained, the treatment of pathological disorders or diseases can beassociated with an affinity for certain sub-types of receptors. Thus theactivation of the MC1 receptors has been associated with the treatmentof inflammations, since their blockage has been associated with thetreatment of cutaneous cancers. The treatment of nutritional disordershas been associated with MC3 and MC4 receptors, the treatment of obesitywith agonists and the treatment of cachexia and anorexia by antagonists.Other indications associated with the activation of MC3 and MC4receptors are sexual activity disorders, neuropathic pain, anxiety,depression and drug addiction. The activation of MC5 receptors has beenassociated with the treatment of acne and dermatoses.

Research efforts have therefore focussed on the discovery of non-peptidecompounds with a low molecular weight, bio-available by oral route,powerful agonists or antagonists of the melanocortin receptors.

The applicants have found that the novel compounds of general formula(I) described hereafter possess a good affinity for the melanocortinreceptors. They act preferentially on MC4 receptors. Said compounds,agonists or antagonists of the melanocortin receptors, can be used fortreating pathological states or metabolic diseases, of the nervous ordermatological system, in which one or more melanocortin receptors areinvolved such as the following examples: inflammatory states, disordersof energy homeostasis, food intake, weight disorders (obesity, cachexia,anorexia), sexual activity disorders (erective disorders), pain and moreparticularly neuropathic pain. There can also be mentioned mentaldisorders (anxiety, depression), drug addiction, skin diseases (acne,dermatoses, cutaneous cancers, melanomas). These compounds can also beused to stimulate nerve regeneration.

A subject of the invention is therefore a compound of general formula(I)

in racemic, enantiomeric form, or any combinations of these forms and inwhich:

-   R₁ and R₂ represent, independently, the hydrogen atom; a    (C₁-C₈)alkyl radical optionally substituted by hydroxy;    (C₂-C₆)alkenyl; a bicycloalkyl; or a radical of formula    —(CH₂)_(n)—X₁ or —X—(CH₂)_(n′)—X′₁;-   X represents —C(O)— or —C(S)—NH—;-   X₁ represents a (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl, adamantyl,    heterocycloalkyl, aryl or heteroaryl radical,    -   the (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl and heteroaryl        radicals being optionally substituted by one or more identical        or different substituents chosen from: —(CH₂)_(n1)—V₁—Y₁, halo,        nitro and cyano;    -   V₁ represents —O—, —S— or a covalent bond;    -   Y₁ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo radicals, or aryl;    -   n and n′ represent an integer from 0 to 6 and n₁ an integer from        0 to 2 (it being understood that when n is equal to 0, then X₁        does not represent the alkoxy radical);-   X′₁ represents the hydrogen atom, a (C₁-C₆)alkyl radical optionally    substituted by one or more identical or different halo radicals,    (C₃-C₇)cycloalkyl; or aryl optionally substituted by one or more    identical or different substituents chosen from: halo, nitro, cyano,    (C₁-C₆)alkyl-carbonyl, (C₁-C₆)alkyl optionally substituted by one or    more identical or different halo radicals, and (C₁-C₆)alkoxy    optionally substituted by one or more identical or different halo    radicals;-   or R₁ and R₂ form together, with the nitrogen atom to which they are    attached, a heterobicycloalkyl or a heterocycloalkyl optionally    substituted by one or more identical or different substituents    chosen from: hydroxy, (C₁-C₆)alkyl optionally substituted by    hydroxy, (C₁-C₆)alkoxy-carbonyl, —(CH₂)_(n″)-A, —C(O)—NV₁′Y₁′, and    heterocycloalkyl; or R₁ and R₂ form together a radical of formula:

-   V₁′ and Y₁′ represent, independently, the hydrogen atom or a    (C₁-C₆)alkyl;-   A represents an aryl radical optionally substituted by one or more    identical or different substituents chosen from: halo, nitro, cyano,    (C₁-C₆)alkyl optionally substituted by one or more identical or    different halo radicals, and (C₁-C₆)alkoxy optionally substituted by    one or more identical or different halo radicals;-   n″ represents an integer from 0 to 2;-   R₃ represents -Z₃, —C(R_(z3))(R′_(z3))-Z₃,    —C(R_(z3))(R′_(z3))—(CH₂)_(p)-Z₃ or —C(O)-Z′₃;    -   R_(z3) and R′_(z3) represent, independently, the hydrogen atom        or a (C₁-C₆)alkyl radical;    -   Z₃ represents Z_(3a), Z_(3b), Z_(3c), Z_(3d), or Z_(3e);    -   Z_(3a) represents a (C₁-C₆)alkyl or (C₂-C₆)alkenyl radical;    -   Z_(3b) represents a (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,        (C₁-C₆)alkylamino or di((C₁-C₆)alkyl)amino radical;    -   Z_(3c) represents an aryl or heteroaryl radical;    -   the aryl and heteroaryl radicals being optionally substituted by        one or more identical or different substituents chosen from:        halo, cyano, nitro, azido, oxy or —(CH₂)_(p′)—V₃—Y₃;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —O(CO)—, —SO₂—,        —SO₂NH—, —NR′₃—SO₂—, —NR′₃—, —NR′₃—C(O)—, —C(O)—NR′₃—,        —NH—C(O)—NR′₃— or a covalent bond;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals; an aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro, (C₁-C₆)alkyl and (C₁-C₆)alkoxy; or an aryl-(C₁-C₆)alkyl        radical optionally substituted by one or more identical or        different substituents chosen from: halo, nitro, (C₁-C₆)alkyl        and (C₁-C₆)alkoxy;    -   Z_(3d) represents a (C₁-C₆)alkoxy-carbonyl, amino-carbonyl,        (C₁-C₆)alkylamino-carbonyl, di((C₁-C₆)alkyl)amino-carbonyl        radical;    -   Z_(3e) represents a (C₁-C₆)alkyl-C(O)—NH—, (C₃-C₇)cycloalkyl,        heterocycloalkyl radical or a radical of formula

-   -   -   the (C₃-C₇)cycloalkyl and heterocycloalkyl radicals being            optionally substituted by one or more identical or different            oxy or (C₁-C₆)alkyl radicals,

    -   Z′₃ represents an aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro and —(CH₂)_(p″)—V′₃—Y′₃;

    -   V′₃ represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR′₃—, —NR′₃—C(O)—,        —NH—C(O)—NR′₃ or a covalent bond;

    -   Y′₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;

    -   R′₃ represents the hydrogen atom, a (C₁-C₆)alkyl or        (C₁-C₆)alkoxy radical;

    -   p, p′ and p″ represent, independently, an integer from 0 to 6;

-   R₄ represents a radical of formula —(CH₂)_(s)—R′₄

-   R′₄ represents a heterocycloalkyl containing at least one nitrogen    atom and optionally substituted by (C₁-C₆)alkyl or aralkyl; a    heteroaryl containing at least one nitrogen atom and optionally    substituted by (C₁-C₆)alkyl; or a radical of formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl; (C₂-C₆)alkenyl;        (C₃-C₇)cycloalkyl optionally substituted by one or more        identical or different (C₁-C₆)alkyl substituents; cyclohexene;        heteroaryl; aryl optionally substituted by one or more identical        or different radicals chosen from: —(CH₂)_(s″)—V₄—Y₄, halo and        nitro;        -   V₄ represents —O—, —S—, —NH—C(O)—, —NV₄′- or a covalent            bond;        -   Y₄ represents a hydrogen atom or a (C₁-C₆)alkyl radical            optionally substituted by one or more identical or different            halo radicals;        -   V₄′ represents a hydrogen atom or a (C₁-C₆)alkyl;        -   s″ represents an integer from 0 to 4;    -   or Z₄ represents a radical of formula

-   -   s and s′ represent, independently, an integer from 0 to 6; or a        pharmaceutically acceptable salt thereof.

In the definitions indicated above, the expression halo represents thefluoro, chloro, bromo or iodo radical, preferably chloro, fluoro orbromo. The expression alkyl (unless otherwise specified), preferablyrepresents a linear or branched alkyl radical having 1 to 6 carbonatoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl, pentyl or amyl, isopentyl, neopentyl,2,2-dimethyl-propyl, hexyl, isohexyl or 1,2,2-trimethyl-propyl radicals.The term (C₁-C₈)alkyl designates a linear or branched alkyl radicalhaving 1 to 8 carbon atoms, such as the radicals containing from 1 to 6carbon atoms as defined above but also heptyl, octyl,1,1,2,2-tetramethyl-propyl, 1,1,3,3-tetramethyl-butyl. By the expressionalkyl substituted by hydroxy, is meant any linear or branched alkylchain, containing a hydroxy radical positioned along the chain; thus fora chain containing 3 carbon atoms and a hydroxy radical, there can begiven as examples HO—(CH₂)₃—, CH₃—CH(OH)—CH₂— and CH₃—CH₂—CH(OH)—.

By alkenyl, unless otherwise specified, is meant a linear or branchedalkyl radical containing 1 to 6 carbon atoms and having at least oneunsaturation (double bond), such as for example vinyl, allyl, propenyl,butenyl or pentenyl.

The term alkoxy designates the radicals in which the alkyl radical is asdefined above such as for example the methoxy, ethoxy, propyloxy orisopropyloxy radicals but also linear, secondary or tertiary butoxy,pentyloxy. The term alkoxy-carbonyl preferably designates the radicalsin which the alkoxy radical is as defined above such as for examplemethoxycarbonyl, ethoxycarbonyl.

The term (C₃-C₇)cycloalkyl designates a saturated carbon monocyclicsystem comprising 3 to 7 carbon atoms, and preferably the cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. The expressionheterocycloalkyl designates a condensed monocyclic or bicyclic saturatedsystem containing from 2 to 9 carbon atoms and at least one heteroatom.This radical can contain several identical or different heteroatoms.Preferably, the heteroatoms are chosen from oxygen, sulphur or nitrogen.As an example of a heterocycloalkyl, there can be mentioned the ringscontaining at least one nitrogen atom such as pyrrolidine,imidazolidine, pyrrazolidine, isothiazolidine, thiazolidine,isoxazolidine, oxazolidine, piperidine, piperazine, azepane(azacycloheptane), azacyclooctane, diazepane, morpholine,decahydroisoquinoline (or decahydroquinoline) but also the ringscontaining no nitrogen atom such as tetrahydrofuran ortetrahydrothiophene. As an illustration of a cycloalkyl orheterocycloalkyl substituted by oxy, there can be mentioned for examplepyrrolidinone and imidazolidinone.

The term bicycloalkyl designates a non-condensed saturated hydrocarbonbicyclic system containing 5 to 9 carbon atoms, such as bicyclo-heptanesuch as for example bicylo[2,2,1]heptane, or bicyclo-octane such as forexample bicyclo[2,2,2]octane or bicyclo[3,2,1]octane. The termheterobicycloalkyl designates a non-condensed saturated hydrocarbonbicyclic system containing 5 to 8 carbon atoms and at least oneheteroatom chosen from nitrogen, oxygen and sulphur. As examples of aheterobicycloalkyl, there can be mentioned aza-bicycloheptane andaza-bicyclooctane such as 7-aza-bicyclo[2,2,1]heptane,2-aza-bicyclo[2,2,2]octane or 6-aza-bicyclo[3,2,1]octane.

The expression aryl represents an aromatic radical, constituted by aring or condensed rings, such as for example the phenyl, naphthyl,fluorenyl or anthryl radical. The expression heteroaryl designates anaromatic radical, constituted by a ring or condensed rings, with atleast one ring containing one or more identical or different heteroatomschosen from sulphur, nitrogen or oxygen. As examples of a heteroarylradical, there can be mentioned the radicals containing at least onenitrogen atom such as pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,thiazolyl, isoxazolyl, oxazolyl, triazolyl, thiadiazolyl, pyridyl,pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, quinoxalinyl, indolyl,dihydroindolyl, benzoxadiazoyl, carbazolyl, phenoxazinyl but also theradicals containing no nitrogen atom such as thienyl, benzothienyl,furyl, benzofuryl, dibenzofuryl, dihydrobenzofuryl, dibenzothienyl,thioxanthenyl, or pyranyl. The term aralkyl (arylalkyl) preferablydesignates the radicals in which the aryl and alkyl radicals are asdefined above such as for example benzyl or phenethyl. As illustrationsof an aryl or heteroaryl radical substituted by oxy, there can bementioned for example fluorenone, acridone, xanthenone,benzothienyl-dione, anthraquinone, thioxanthene, benzocoumarin.

In the present Application also, the (CH₂)_(i) radical (i being aninteger which can represent n, n′, n″, n₁, p, p′, p″, s, s′ and s″ asdefined above), represents a linear or branched hydrocarbon chain with icarbon atoms. Thus the —(CH₂)₃— radical can represent —CH₂—CH₂—CH₂— butalso —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)— or —C(CH₃)₂—.

According to the present Application also, when a radical has theformula —B-D-E with D representing for example —C(O)—NH—, this meansthat the carbon atom of —C(O)—NH— is bound to B and the nitrogen atom toE.

Preferably, the invention relates to a compound of formula I as definedabove, characterized in that

-   R₁ and R₂ represent, independently, the hydrogen atom, a    (C₁-C₈)alkyl radical, a bicycloalkyl or a radical of formula    —(CH₂)_(n)—X₁ or —X—(CH₂)_(n′)—X′₁;-   X represents —C(O)— or —C(S)—NH—;-   X₁ represents a (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl radical optionally    substituted by a (C₁-C₆)alkyl, or heteroaryl;-   X′₁ represents the hydrogen atom, a (C₁-C₆)alkyl radical optionally    substituted by one or more identical or different halo radicals,    (C₃-C₇)cycloalkyl or aryl optionally substituted by a    (C₁-C₆)alkyl-carbonyl;-   or R₁ and R₂ form together, with the nitrogen atom to which they are    attached, a heterobicycloalkyl or a heterocycloalkyl optionally    substituted by one or more identical or different substituents    chosen from: (C₁-C₆)alkyl, (C₁-C₆)alkoxy-carbonyl and —(CH₂)_(n″)-A;-   A represents an aryl radical optionally substituted by one or more    identical or different substituents chosen from: halo and    (C₁-C₆)alkyl;-   n″ represents an integer from 0 to 1;-   R₄ represents a radical of formula —(CH₂)_(s)—R′₄-   R′₄ represents a heterocycloalkyl containing at least one nitrogen    atom and optionally substituted by (C₁-C₆)alkyl; or a radical of    formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl or aryl optionally        substituted by one or more identical or different radicals        chosen from: —(CH₂)_(s″)—V₄—Y₄;        -   V₄ represents —O—;        -   Y₄ represents a (C₁-C₆)alkyl radical optionally substituted            by one or more identical or different halo radicals;        -   s″ represents an integer from 0 to 4;    -   s and s′ represent, independently, an integer from 1 to 4; or a        salt; or a pharmaceutically acceptable salt thereof,        and more particularly compound I comprises at least one of the        following characteristics:    -   the cycloalkyl radical is chosen from cyclopropyl, cyclobutyl        and cyclohexyl;    -   the bicycloalkyl radical is bicylo[2,2,1]heptane;    -   the heterobicycloalkyl is 7-aza-bicyclo[2,2,1]heptane;    -   the aryl radical is the phenyl radical;    -   the heteroaryl radical is the furyl radical;    -   the heterocycloalkyl is chosen from piperidine, morpholine and        piperazine; or a pharmaceutically acceptable salt thereof.

Very preferentially also, the invention relates to a compound of formulaI as defined above, characterized in that

-   -   R₁ and R₂ represent, independently, the hydrogen atom, a        (C₁-C₈)alkyl radical or a radical of formula —(CH₂)_(n)—X₁ or        —X—(CH₂)_(n′)—X′₁;    -   X represents —C(O)—;    -   X₁ represents a (C₃-C₇)cycloalkyl radical;    -   X′₁ represents the hydrogen atom or a (C₃-C₇)cycloalkyl radical;    -   n represents 0 or 1; n′ represents an integer from 0 to 5;    -   or R₁ and R₂ form together, with the nitrogen atom to which they        are attached, a heterocycloalkyl optionally substituted by one        or more identical or different (C₁-C₆)alkyl substituents;        and more particularly the (C₃-C₇)cycloalkyl radical represented        by X₁ and X′₁ is chosen from cyclopropyl, cyclobutyl and        cyclohexyl; and the heterocycloalkyl that R₁ and R₂ form        together, is the piperidine ring; or a pharmaceutically        acceptable salt thereof.

Very preferentially also, the invention relates to a compound of formulaI as defined above, characterized in that

-   R₄ represents a radical of formula —(CH₂)_(s)—R′₄-   R′₄ represents a heterocycloalkyl containing at least one nitrogen    atom and optionally substituted by (C₁-C₆)alkyl; or a radical of    formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   s and s′ represent, independently, an integer from 2 to 4;        and more particularly the heterocycloalkyl represented by R′₄ is        chosen from: piperidine and morpholine; or a pharmaceutically        acceptable salt thereof.

Preferably also, the invention relates to a compound of formula I asdefined above, characterized in that R₃ represents —C(O)-Z′₃

-   -   Z′₃ represents an aryl radical optionally substituted by one or        more identical or different substituents chosen from halo and        —(CH₂)_(p″)—V′₃—Y′₃;    -   V′₃ represents —O— or a covalent bond;    -   Y′₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   p″ represents an integer from 0 to 2; or a pharmaceutically        acceptable salt thereof.

Preferably also, the invention relates to a compound of formula I asdefined above, characterized in that R₃ represents -Z₃,—C(R_(z3))(R′_(z3))-Z₃ or —C(R_(z3))(R′_(z3))—(CH₂)_(p)-Z₃; or apharmaceutically acceptable salt thereof.

Very preferentially also, the invention relates to a compound of formulaI as defined above, characterized in that R₃ represents -Z₃ and Z₃represents Z_(3b), Z_(3c) or Z_(3e); and preferably Z₃ represents Z_(3c)and Z_(3c) represents an aryl radical,

and more particularly Z_(3c) represents a phenyl radical beingoptionally substituted by one or more identical or differentsubstituents chosen from: halo, nitro or —(CH₂)_(p′)—V₃—Y₃;

-   -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —SO₂NH—, —NR′₃—C(O)—,        —C(O)—NR′₃— or a covalent bond;    -   R′₃ represents the hydrogen atom;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;        and more particularly also Z_(3c) represents a phenyl radical        substituted by one or more identical or different substituents        of formula —(CH₂)_(p′)—V₃—Y₃;    -   V₃ represents —C(O)—, —C(O)—O— or —C(O)—NR′₃—;    -   R′₃ represents the hydrogen atom;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical; or a        pharmaceutically acceptable salt thereof.

Very preferentially also, the invention relates to compounds of formulaI as defined above, characterized in that R₃ represents—C(R_(z3))(R′_(z3))-Z₃ and Z₃ represents Z_(3d) or Z_(3e); or apharmaceutically acceptable salt thereof.

Very preferentially also, the invention relates to compounds of formulaI as defined above, characterized in that R₃ represents—C(R_(z3))(R′_(z3))—(CH₂)_(p)-Z₃ and Z₃ represents Z_(3c), Z_(3d) orZ_(3e),

and more particularly Z₃ represents Z_(3d) or Z_(3e)

-   -   Z_(3d) represents a (C₁-C₆)alkoxy-carbonyl or amino-carbonyl        radical;    -   Z_(3e) represents a (C₁-C₆)alkyl-C(O)—NH—, heterocycloalkyl        radical being optionally substituted by an oxy radical, or a        radical of formula

or a pharmaceutically acceptable salt thereof.

In the present Application, the symbol ->* corresponds to the attachmentpoint of the radical. When the attachment site is not specified on theradical, this means that the attachment is carried out on one of theavailable sites of this radical for such an attachment.

According to the definitions of the variable groups R₁, R₂, R₃ and R₄,the compounds according to the invention can be prepared in liquid phaseaccording to the different procedures A to E described below.

A. Preparation According to Reaction Diagram A:

As described in diagram A, 2,6-dichloro-3-nitropyridine can be treatedwith a primary amine in the presence of an organic base such as atertiary amine or an inorganic base such as potassium or caesiumcarbonate, in an apolar aprotic solvent such as toluene at a temperatureof approximately 20° C. for 3-18 hours in order to produce compound (1).The chlorinated derivative (1) can react with a primary or secondaryamine, in the presence of an organic base such as a tertiary amine or aninorganic base such as potassium or caesium carbonate, in a polaraprotic solvent such as acetonitrile, dimethylformamide or HMPA at atemperature of 20-70° C. for 2-18 hours in order to produce compound(2). The nitro function of compound (2) is reduced by catalytichydrogenation in the presence of 10% palladium on carbon in an inertsolvent such as methanol, ethanol, ethyl acetate or a mixture of thesesolvents, at a temperature of 18-25° C., for 2 to 8 hours in order toproduce the dianiline (3). Derivative (3) is then treated with anisothiocyanate in the presence of a coupling agent supported or notsupported on a resin such as diisopropylcarbodiimide- ordicyclohexylcarbodiimide or N-cyclohexylcarbodiimide N-methylpolystyrene resin in an inert solvent such as tetrahydrofuran, methylenechloride, or chloroform at a temperature of 20-70° C. for 2 to 72 hoursin order to produce derivative (4). Alternatively, derivative (3) can betreated with an isothiocyanate in an inert solvent such astetrahydrofuran, methylene chloride, chloroform or ethanol at atemperature of 20-80° C. for 1-16 hours then the resultant thiourea canbe treated with yellow mercury(II) oxide in the presence of a catalyticquantity of sulphur in a polar solvent such as methanol or ethanol for 2to 24 hours at a temperature of 20-80° C. in order to produce (4).

EXAMPLE A14-{[3-(3-aminopropyl)-5-(diisobutylamino)-3H-imidazo[4,5-b]pyridin-2-yl]amino}-N-methylbenzamidehydrochloride

Stage 1: tert-butyl 3-[(6-chloro-3-nitropyridin-2-yl)amino]propylcarbamate

Potassium carbonate (5.4 g, 1.2 eq) andtert-butyl-N(2-aminopropyl)carbamate (6.8 g, 1 eq) are addedsuccessively to 2,6-dichloro-3-nitropyridine (8 g, 1 eq) in solution intoluene (150 ml). After stirring for 6 hours at a temperature ofapproximately 20° C., the mixture is concentrated under reduced pressureat 40° C. then water (80 ml) and dichloromethane (200 ml) are added.After decantation and extractions, the combined organic phases arewashed with salt water, dried over Na₂SO₄ then concentrated underreduced pressure at 40° C. Purification of the solid obtained, by flashchromatography on silica gel (eluent: heptane/ethyl acetate 7:3),produces the expected compound in the form of a yellow solid (11.4 g;92% yield).

MS/LC: calculated MM=330.7; m/z=331.1 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 1.36 (s, 9H), 1.68 (m, 2H), 2.99 (dd, 2H), 3.51 (dd, 2H), 6.76 (d,1H), 6.86 (t, 1H), 8.41 (d, 1H), 8.75 (t, 1H).

Stage 2: tert-butyl3-{[6-(diisobutylamino)-3-nitropyridin-2-yl]amino}propyl carbamate

Potassium carbonate (1.31 g, 1.5 eq) and diisobutylamine (981 mg, 1.2eq) are added successively to a solution of tert-butyl3-[(6-chloro-3-nitropyridin-2-yl)amino]propyl carbamate (2 g, 1 eq) inacetonitrile (100 ml). The mixture is heated to reflux for 5 hours thencooled down to ambient temperature and concentrated under reducedpressure at 40° C. The residue is taken up in dichloromethane (200 ml)and water (90 ml). After decantation and extractions, the combinedorganic phases are washed with salt water, dried over Na₂SO₄ thenconcentrated under reduced pressure at 40° C. Purification of theresidue obtained, by flash chromatography on silica gel (eluent:heptane/ethyl acetate 7:3 to 1:1), produces the expected compound in theform of a yellow oil (2.46 g; 95% yield).

MS/LC: calculated MM=437.6; m/z=438.3 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.86 (m, 12H), 1.36 (s, 9H), 1.68 (m, 2H), 1.99 (m, 1H), 2.15 (m, 1H),2.98 (dd, 2H), 3.35 (m, 2H), 3.48 (m, 4H), 6.20 (d, 1H), 6.85 (t, 1H),8.01 (d, 1H), 8.85 (t, 1H).

Stage 3: tert-butyl3-[5-(diisobutylamino)-2-({4-[(methylamino)carbonyl]phenyl}amino)-3H-imidazo[4,5-b]pyridin-3-yl]propylcarbamate

Tert-butyl 3-{[6-(diisobutylamino)-3-nitropyridin-2-yl]amino}propylcarbamate (63 mg) in solution in a mixture of ethyl acetate/ethanol 3:1(1.5 ml), and 10% palladium on carbon (7 mg) are added to a hemolysistube placed in an autoclave. After stirring for 3 hours under a hydrogenatmosphere (3 bar) at a temperature of approximately 20° C., the mixtureis filtered on celite in a hemolysis tube containing a solution of4-isothiocyanato-N-methylbenzamide (43 mg, 1.2 eq) in tetrahydrofuran (1ml). N-cyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; load 1.9 mmol/g; 237 mg, 3 eq) is added to the filtratethus obtained. The mixture is heated to reflux for 18 hours, cooled downto ambient temperature then filtered on frit and the filtrate isconcentrated under reduced pressure at 40° C. Purification of theresidue by flash chromatography on silica gel (eluent: heptane/ethylacetate 1:1 to 100% ethyl acetate) produces the expected compound (53mg; 65% yield).

MS/LC: calculated MM=551.7; m/z=552.3 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.88 (d, 12H), 1.36 (s, 9H), 1.83 (m, 2H), 2.09 (m, 2H), 2.76 (d, 3H),2.98 (m, 2H), 3.35 (m, 4H), 4.15 (t, 2H), 6.34 (d, 1H), 6.80 (t, 1H),7.51 (d, 1H), 7.78 (AB, 2H), 7.85 (AB, 2H), 8.20 (m, 1H), 8.97 (s, 1H).

Stage 4:4-{[3-(3-aminopropyl)-5-(diisobutylamino)-3H-imidazo[4,5-b]pyridin-2-yl]amino}-N-methylbenzamidehydrochloride

A solution of hydrochloric acid in ether (1N, 2 ml) is added to asolution of tert-butyl3-[5-(diisobutylamino)-2-({4-[(methylamino)carbonyl]phenyl}amino)-3H-imidazo[4,5-b]pyridin-3-yl]propylcarbamate (51 mg) in ethyl acetate (0.5 ml). After stirring for 2 hoursat a temperature of approximately 20° C., the mixture is filtered andthe solid obtained is washed with ethyl ether and dried (50 mg; 95%yield).

MS/LC: calculated MM=451.6; m/z=452.3 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.88 (d, 12H), 2.10-2.19 (m, 4H), 2.79 (d, 3H), 2.95 (m, 2H), 3.35 (m,4H), 4.40 (t, 2H), 6.55 (d, 1H), 7.53 (d, 1H), 7.64 (m, 2H), 7.94 (m,5H), 8.45 (m, 2H).

EXAMPLE A21-(4-{[5-(dibutylamino)-3-(3-piperidin-1-ylpropyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino}phenyl)ethanonehydrochloride

Stage 1: 6-chloro-3-nitro-N-(3-piperidin-1-ylpropyl)pyridin-2-amine

Potassium carbonate (540 mg, 1.5 eq) and 3-piperidino-propylamine (420mg, 1 eq) are added successively to 2,6-dichloro-3-nitropyridine (500mg, 1 eq) in solution in toluene (10 ml). After stirring for 2 hours ata temperature of approximately 20° C., the mixture is concentrated underreduced pressure at 40° C. then water (20 ml) and dichloromethane (70ml) are added. After decantation and extractions, the combined organicphases are washed with salt water, dried over Na₂SO₄ then concentratedunder reduced pressure at 40° C. Purification of the solid obtained, byflash chromatography on silica gel (eluent: heptane/ethyl acetate 3:7 to100% ethyl acetate), produces the expected compound in the form of ayellow solid (473 mg; 61% yield).

MS/LC: calculated MM=298.8; m/z=299.1 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 1.37 (m, 2H), 1.49 (m, 4H), 1.74 (m, 2H), 2.34 (m, 6H), 3.55 (m, 2H),6.75 (d, 1H), 8.40 (d, 1H), 8.96 (t, 1H).

Stage 2:N⁶,N⁶-dibutyl-3-nitro-N²-(3-piperidin-1-ylpropyl)pyridine-2,6-diamine

Potassium carbonate (54 mg, 2 eq) and a solution of dibutylamine (30 mg,1.2 eq) in acetonitrile (2 ml) are added successively to a solution of6-chloro-3-nitro-N-(3-piperidin-1-ylpropyl)pyridin-2-amine (59 mg, 1 eq)in acetonitrile (3 ml). The mixture is heated to reflux for 15 hoursthen cooled down to ambient temperature and concentrated under reducedpressure at 40° C. The residue is taken up in dichloromethane (200 ml)and water (90 ml). After decantation and extractions, the combinedorganic phases are washed with salt water, dried over Na₂SO₄ thenconcentrated under reduced pressure at 40° C. Purification of theresidue obtained, by flash chromatography on silica gel (eluent:heptane/ethyl acetate 1:1 to 100% ethyl acetate), produces the expectedcompound (73 mg; 95% yield).

MS/LC: calculated MM=391.6; m/z=392.2 (MH+)

Stage 3:1-(4-{[5-(dibutylamino)-3-(3-piperidin-1-ylpropyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino}phenyl)ethanonehydrochloride

N⁶,N⁶-dibutyl-3-nitro-N²-(3-piperidin-1-ylpropyl)pyridine-2,6-diamine(70 mg) in solution in a mixture of ethyl acetate/methanol 3:1 (2 ml),and 10% palladium on carbon (7 mg) are introduced into a hemolysis tubeplaced in an autoclave. After stirring for 3 hours under a hydrogenatmosphere (3 bar) at a temperature of approximately 20° C., the mixtureis filtered on celite in a hemolysis tube containing a solution of4-isothiocyanato-N-methylbenzamide (43 mg, 1.2 eq) in tetrahydrofuran (1ml).

N-cyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; load 1.9 mmol/g; 284 mg, 3 eq) is added to the filtratethus obtained. The mixture is heated to reflux for 18 hours, cooled downto ambient temperature then filtered on frit and the filtrate isconcentrated under reduced pressure at 40° C. Purification of theresidue by flash chromatography on silica gel (eluent: 100%dichloromethane to dichloromethane/methanol 9:1) produces the expectedcompound in the form of a base. The corresponding hydrochloride salt isformed by adding a 1N hydrochloric acid solution in ethyl ether. Theprecipitate obtained is filtered and dried in order to produce theexpected compound (72 mg).

MS/LC: calculated MM=504.7; m/z=505.2 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.92 (t, 6H), 1.34 (m, 5H), 1.55 (m, 4H), 1.77 (m, 5H), 2.35 (m, 2H),2.59 (s, 3H), 2.88 (m, 2H), 3.18 (m, 2H), 3.38 (m, 2H), 3.49 (m, 4H),4.48 (t, 2H), 6.60 (m, 1H), 7.59 (d, 1H), 7.70 (d, 2H), 8.06 (m, 2H),10.62 (s, 1H), 11.71 (s, 1H).

Preparation of Non-Commercial Isothiocyanates:

A primary amine can be converted to isothiocyanate, by treatment withthiophosgene in the presence of a tertiary base such as triethylamine,in an aprotic solvent such as dichloromethane or tetrahydrofuran, at atemperature of 0-20° C. for 0.3 to 2 hours, or alternatively bytreatment with carbon disulphide and cyclohexylcarbodiimide supported ornot supported on a resin in an aprotic solvent such as dichloromethaneor tetrahydrofuran, at a temperature of 0-70° C. for 0.3 to 15 hours.

Preparation of 4-isothiocyanato-N-methylbenzamide:

Thiophosgene (1.13 ml, 1.1 eq) is added dropwise to a solution cooleddown to 0° C., of 4-amino-N-methylbenzamide (2 g, 1 eq) andtriethylamine (5.6 ml, 3 eq) in tetrahydofuran (260 ml). The mixture isstirred for 30 minutes at 0° C. then the cold bath is removed andstirring is continued for another 30 minutes. Water (100 ml) and diethylether (250 ml) are added to the mixture. After decantation andextractions, the organic phases are combined, washed with salt water,dried over Na₂SO₄ then concentrated under reduced pressure at 40° C. Thesolid obtained is recrystallized from a dichloromethane/petroleum ethermixture (2.2 g; 86% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 2.77 (d, 3H), 7.51 (AB, 2H), 7.88 (AB,2H), 8.52 (m, 1H).

According to the same procedure as that described forN-(4-isothiocyanatophenyl)acetamide, the following isothiocyanates canbe prepared:

Preparation of N-(4-isothiocyanatophenyl)-N′-methoxyurea:

Carbonyldiimidazole (CDI) (1.62 g, 2 eq) is added to a solution cooleddown to 0° C. of tert-butyl 4-aminophenyl carbamate (1.04 g) inanhydrous dichloromethane (100 ml). The mixture is taken to atemperature of 20° C. and stirred at this temperature for 15 hours.Triethylamine (7 ml, 10 eq) followed by O-methylhydroxylaminehydrochloride (4.2 g, 10 eq) are added successively to the reactionmedium cooled down to 0° C. After stirring for 3 hours at a temperatureof approximately 20° C., water saturated in sodium hydrogen carbonateand chloroform is added to the mixture. After decantation andextractions, the combined organic phases are washed with salt water,dried over Na₂SO₄ then concentrated under reduced pressure at 40° C. inorder to produce tert-butyl 4-{[(methoxyamino)carbonyl]amino}phenylcarbamate (1.33 g). A flow of gaseous hydrochloric acid is passedthrough a suspension of this derivative in ethyl acetate until thereaction is complete. The precipitate obtained is filtered then washedwith diethyl ether and dried in order to produceN-(4-aminophenyl)-N′-methoxyurea hydrochloride (1 g).

Thiophosgene (0.38 ml, 1.1 eq) is added dropwise to a solution cooleddown to 0° C., of N-(4-aminophenyl)-N′-methoxyurea hydrochloride (1 g)and triethylamine (3.2 ml, 5 eq) in tetrahydofuran (90 ml). The mixtureis stirred for 15 minutes at 0° C. then water and diethyl ether areadded. After decantation and extractions, the organic phases arecombined, washed with salt water, dried over Na₂SO₄ then concentratedunder reduced pressure at 40° C. Purification by flash chromatography onsilica gel (eluent: heptane/ethyl acetate 7:3 to 3:7) produces theexpected compound (630 mg; 62% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 3.61 (s, 3H), 7.34 (AB, 2H), 7.67 (AB,2H), 9.11 (s, 1H), 9.65 (s, 1H).

Preparation of Non-Commercial Acyl-isothiocyanates:

Acyl-isothiocyanates can be prepared from the corresponding acidchlorides by treatment with potassium thiocyanate in an aprotic solventsuch as acetonitrile at a temperature of 0-60° C. for 0.2-5 hours.

Methyl-4-isothiocyanatocarbonylbenzoate:

Potassium thiocyanate (1.08 g, 1.1 eq) is added to a solution ofmethyl-4-chlorocarbonylbenzoate (2 g) in acetonitrile (30 ml). Afterstirring for 1 hour at approximately 20° C., the mixture is filtered andthe filtrate is concentrated under reduced pressure at 40° C. The solidobtained is purified by flash chromatography on silica gel (eluent:heptane/ethyl acetate 1:1) in order to produce the expected compound(2.1 g; 95% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 3.88 (s, 3H), 8.0 (m, 4H).

According to the same procedure as that described formethyl-4-isothiocyanatocarbonylbenzoate, the following isothiocyanatescan be prepared:

According to reaction diagram A and in a manner analogous to theprocedure described for the synthesis of4-{[3-(3-aminopropyl)-5-(diisobutylamino)-3H-imidazo[4,5-b]pyridin-2-yl]amino}-N-methylbenzamidehydrochloride or1-(4-{[5-(dibutylamino)-3-(3-piperidin-1-ylpropyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino}phenyl)ethanonehydrochloride, the following compounds can be prepared:

-   in which R₁R₂N represents one of the radicals below:

-   R₃ represents one of the radicals below:

-   -   1 or more substitutions chosen from:    -   U=H, F, Cl, Br, I, NO₂, OMe, SMe, Me, Et, iPr, tBu, CF₃, OCF₃,        C(O)OMe, C(O)OEt, C(O)Me, C(O)Et, NHC(O)Me, C(O)NHMe, C(O)NH₂,        S(O)₂NH₂, NHC(O)NHMe, NHC(O)NHOMe

-   -   W=H, F, Cl, Br, NO₂, Me, OMe, OEt, CF₃, OCF₃, tBu, C(O)Me,        C(O)OMe, C(O)NHMe

-   and R₄ represents one of the radicals below:

B. Preparation According to Reaction Diagram B:

As described in diagram B, derivative (5), prepared according toreaction diagram A can be treated with an organic or inorganic acid suchas trifluoroacetic acid or hydrochloric acid (aqueous or in gaseousform) in an aprotic solvent such as dichloromethane, diethyl ether orethyl acetate at a temperature of 0-20° C. for 0.5 to 5 hours, in orderto produce the amine (6). The amine (6) can react with an aldehyde in aprotic or aprotic solvent, such as dichloromethane, tetrahydrofuran ormethanol, for 1 to 15 hours at a temperature of 0-50° C. The resultantimine is then reduced in situ by a reducing agent supported or notsupported on a resin, preferably sodium triacetoxyborohydride, sodiumcyanoborohydride or borohydride supported on a resin, with or withoutthe presence of an acid such as acetic acid, at a temperature of 20 to50° C. for a duration of 0.2 to 5 hours, in order to produce compound(7). The secondary amine (7) can optionally undergo a second reducingamination under the same operating conditions as those describedpreviously in order to produce the tertiary amine (7′).

EXAMPLE B13-{2-[(4-methoxybenzyl)amino]ethyl}-N⁵,N⁵-bis(3-methylbutyl)-N²-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridine-2,5-diamine

Stage 1: tert-butyl 2-[(6-chloro-3-nitropyridin-2-yl)amino]ethylcarbamate

Potassium carbonate (8.3 g, 1.2 eq) andtert-butyl-N(2-aminoethyl)carbamate (8 g, 1 eq) are added successivelyto 2,6-dichloro-3-nitropyridine (10.2 g, 1 eq) in solution in toluene(200 ml). After stirring for 4 hours at a temperature of approximately20° C., the mixture is concentrated under reduced pressure at 40° C.then water (130 ml) and dichloromethane (250 ml) are added. Afterdecantation and extractions, the combined organic phases are washed withsalt water, dried over Na₂SO₄ then concentrated under reduced pressureat 40° C. Purification of the solid obtained, by flash chromatography onsilica gel (eluent: heptane/ethyl acetate 7:3), produces the expectedcompound in the form of a yellow solid (12.5 g; 79% yield).

MS/LC: calculated MM=316.7; m/z=317.1 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 1.34 (s, 9H), 3.19 (dd, 2H), 3.56 (dd, 2H), 6.78 (d, 1H), 6.94 (t,1H), 8.41 (d, 1H), 8.68 (t, 1H).

Stage 2: tert-butyl2-({6-[bis(3-methylbutyl)amino]-3-nitropyridin-2-yl}amino)ethylcarbamate

Potassium carbonate (207 mg, 1.5 eq) and diisoamylamine (188 mg, 1.2 eq)are added successively to a solution of tert-butyl2-[(6-chloro-3-nitropyridin-2-yl)amino]ethylcarbamate (316 mg, 1 eq) inacetonitrile (10 ml). The mixture is heated to reflux for 5 hours thencooled down to ambient temperature and concentrated under reducedpressure at 40° C. The residue is taken up in dichloromethane (50 ml)and water (15 ml). After decantation and extractions, the combinedorganic phases are washed with salt water, dried over Na₂SO₄ thenconcentrated under reduced pressure at 40° C. Purification of theresidue obtained, by flash chromatography on silica gel (eluent:heptane/ethyl acetate 9:1 to 7:3), produces the expected compound (430mg; 98% yield).

MS/LC: calculated MM=437.6; m/z=438.3 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.91 (d, 12H), 1.35 (s, 9H), 1.45 (m, 4H), 1.60 (m, 2H), 3.17 (m, 2H),3.40 (m, 2H), 3.56 (m, 4H), 6.10 (d, 1H), 6.93 (t, 1H), 8.04 (d, 1H),8.83 (t, 1H).

Stage 4: tert-butyl2-{5-[bis(3-methylbutyl)amino]-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate

Tert-butyl2-({6-[bis(3-methylbutyl)amino]-3-nitropyridin-2-yl}amino)ethylcarbamate (400 mg, 1 eq) in solution in a mixture of ethylacetate/ethanol 2:1 (60 ml), and 10% palladium on carbon (40 mg) areintroduced into an autoclave. After stirring for 5 hours under ahydrogen atmosphere (3 bar) at a temperature of approximately 20° C.,the mixture is filtered on celite in a flask containing3,4,5-trimethoxyphenyl-isothiocyanate (248 mg, 1.2 eq). The filtrate isconcentrated under reduced pressure at 40° C. then the residue isdiluted in tetrahydrofuran (50 ml) andN-cyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; load 1.9 mmol/g; 1.92 g, 4 eq) is added. The mixture isheated to reflux for 8 hours then cooled down to ambient temperature andfiltered on frit. The filtrate is concentrated under reduced pressure at40° C. Purification of the residue by flash chromatography on silica gel(eluent: heptane/ethyl acetate 9:1 to 6:4) produces the expectedcompound (324 mg; 59% yield).

MS/LC: calculated MM=598.8; m/z=599.4 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.93 (d, 12H), 1.28 (s, 9H), 1.45 (m, 4H), 1.60 (m, 2H), 3.29 (m, 2H),3.43 (m, 4H), 3.61 (s, 3H), 3.77 (s, 6H), 4.17 (t, 2H), 6.24 (d, 1H),6.90 (t, 1H), 7.21 (s, 2H), 7.45 (d, 1H), 8.54 (s, 1H).

Stage 5:3-(2-aminoethyl)-N⁵,N⁵-bis(3-methylbutyl)-N²-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridine-2,5-diamine

A solution of hydrochloric acid in dioxane (4N, 3 ml) is added to asolution of tert-butyl2-{5-[bis(3-methylbutyl)amino]-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate (300 mg) in ethyl acetate (6 ml). After stirring for 4 hoursat a temperature of approximately 20° C., the mixture is filtered. Thesolid obtained is washed with diethyl ether. The hydrochloride thusobtained is taken up in dichloromethane and water saturated with sodiumhydrogen carbonate. After decantation and extractions, the combinedorganic phases are washed with salt water, dried over Na₂SO₄ thenconcentrated under reduced pressure at 40° C. in order to produce theexpected compound in the form of a free base (237 mg, 95% yield).

MS/LC: calculated MM=498.7; m/z=499.3 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.93 (d, 12H), 1.45 (m, 4H), 1.59 (m, 2H), 2.98 (t, 2H), 3.35 (t, 4H),3.61 (s, 3H), 3.77 (s, 6H), 4.10 (t, 2H), 6.23 (d, 1H), 7.16 (s, 2H),7.44 (d, 1H).

Stage 6:3-{2-[(4-methoxybenzyl)amino]ethyl}-N⁵,N⁵-bis(3-methylbutyl)-N²-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridine-2,5-diamine

A solution of3-(2-aminoethyl)-N⁵,N⁵-bis(3-methylbutyl)-N²-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridine-2,5-diamine(83 mg, 1 eq) and p-anisaldehyde (25 mg, 1 eq) in dichloromethane (1.5ml) is stirred for 6 hours at a temperature of approximately 20° C. Themixture is diluted with methanol (2 ml) then sodiumtriacetoxyborohydride (70 mg, 2 eq) is added. After stirring for 0.5hour at a temperature of approximately 20° C., dichloromethane (20 ml)and water saturated with sodium hydrogen carbonate (10 ml) are added tothe mixture. After decantation and extractions, the combined organicphases are washed with salt water, dried over Na₂SO₄ then concentratedunder reduced pressure at 40° C. Purification of the residue by flashchromatography on silica gel (eluent: heptane/ethyl acetate 1:1 to 2:8)produces the expected compound (70 mg, 68% yield).

MS/LC: calculated MM=618.8; m/z=619.4 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.92 (d, 12H), 1.44 (m, 4H), 1.57 (m, 2H), 2.89 (t, 2H), 3.44 (t, 4H),3.60 (s, 3H), 3.70 (m, 8H), 4.19 (t, 2H), 6.23 (d, 1H), 6.80 (d, 2H),7.06 (s, 2H), 7.18 (d, 2H), 7.45 (d, 1H), 9.90 (m, 1H).

C. Preparation According to Reaction Diagram C:

The compounds (7) for which s=3 can also be prepared according to thefollowing diagram C:

As described in diagram C, derivative (8) prepared according to reactiondiagram A can be treated either with an organic acid such as pyridiniumtosylate or paratoluenesulphonic acid in an aprotic solvent such asacetone in the presence of water, at a temperature of 20-70° C. for 2 to12 hours, or by an inorganic acid such as aqueous hydrogen chloride inan aprotic solvent such as tetrahydrofuran at a temperature of 0-20° C.for 6 to 18 hours in order to produce compound (9). The aldehyde (9) canthen be treated with an amine in a protic or aprotic solvent such asdichloromethane, tetrahydrofuran or methanol for 1 to 18 hours at atemperature of 20° C. The resultant imine is then reduced in situ by areducing agent, preferably sodium triacetoxyborohydride or sodiumcyanoborohydride, in the presence or absence of an acid such as aceticacid, at a temperature of 20-50° C. for a duration of 0.2 to 6 hours, inorder to produce compound (10). The secondary amine (10) can optionallyundergo a second reducing amination under the same operating conditionsas those described previously in order to produce the tertiary amine(10′).

According to reaction diagram B or C, the following compounds can beprepared:

-   in which R₁R₂N represents one of the radicals below:

-   R₃ represents one of the radicals below:

-   and R₄ represents one of the radicals below:

D. Preparation According to Reaction Diagram D:

As described in diagram D, the chlorinated derivative (1) preparedaccording to reaction diagram A, can be converted to aniline (11) bytreatment with trifluoroacetamide, in the presence of an inorganic basesuch as caesium or potassium carbonate and a phase transfer catalystsuch as tetrabutylammonium bromide, in a polar aprotic solvent such asdimethylformamide, at a temperature of 80-110° C. for 2-6 hours. Theaniline (11) can be protected in the form of trifluoroacetamide bytreatment with trifluoroacetic anhydride in the presence of a tertiaryamine such as triethylamine or pyridine in an aprotic solvent such asdichloromethane at a temperature of 0-20° C. for 0.2-2 hours, in orderto produce compound (12). The nitro derivative (12) is reduced bycatalytic hydrogenation in the presence of 10% palladium on carbon in aninert solvent such as methanol, ethanol, ethyl acetate or a mixture ofthese solvents, at a temperature of 18-25° C., for 2 to 8 hours in orderto produce the dianiline (13). Derivative (13) is then treated with anisothiocyanate in the presence of a coupling agent supported or notsupported on a resin such as diisopropylcarbodiimide ordicyclohexylcarbodiimide or N-cyclohexylcarbodiimide N-methylpolystyrene resin in an inert solvent such as tetrahydrofuran, methylenechloride, or chloroform at a temperature of 20-70° C. for 2 to 72 hoursin order to produce derivative (14). The trifluoroacetamide (14) ishydrolysed in the presence of potassium or sodium carbonate in a polarprotic solvent such as methanol or ethanol in the presence of water, ata temperature of 50-80° C. for 8-32 hours in order to produce theaniline (15). The aniline (15) can react with an acid chloride in anaprotic solvent such as dichloromethane or tetrahydrofuran in thepresence of a base such as a tertiary amine supported or not supportedon a resin, such as triethylamine or morpholino-methylpolystyrene resin,at a temperature of 040° C. for 0.3-2 hours in order to produce theamide (16). The aniline (15) can also react with a isothiocyanate in anaprotic solvent such as tetrahydrofuran at a temperature of 20-70° C.for 5-24 hours in order to produce the thiourea (17).

EXAMPLE D1N-{3-(2-aminoethyl)-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-5-yl}-2-propylpentanamidehydrochloride

Stage 1: tert-butyl 2-[(6-amino-3-nitropyridin-2-yl)amino]ethylcarbamate

Potassium carbonate (0.87 mg, 1 eq), tetrabutylammonium bromide (0.2 g,0.1 eq) and trifluoroacetamide (1.4 g, 2 eq) are added successively to asolution of tert-butyl 2-[(6-chloro-3-nitropyridin-2-yl)amino]ethylcarbamate prepared according to Example B1, (2 g, 1 eq) indimethylformamide (100 ml). The mixture is heated for 4 hours at 100° C.then cooled down to ambient temperature and filtered on frit. Thefiltrate is concentrated under reduced pressure at 40° C. then water (40ml) and dichloromethane (100 ml) are added to the residue obtained.After decantation and extractions, the combined organic phases arewashed with salt water, dried over Na₂SO₄ then concentrated underreduced pressure at 40° C. Purification of the solid obtained, by flashchromatography on silica gel (eluent: heptane/ethyl acetate 6:4),produces the expected compound (1.21 g; 64% yield).

MS/LC: calculated MM=297.3; m/z=298.2 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 1.35 (s, 9H), 3.17 (dd, 2H), 3.53 (dd, 2H), 5.90 (d, 1H), 6.93 (t,1H), 7.38 (m, 2H), 7.98 (d, 1H), 8.88 (t, 1H).

Stage 2: tert-butyl2-({3-nitro-6-[(trifluoroacetyl)amino]pyridin-2-yl}amino)ethyl carbamate

Triethylamine (0.59 ml) then trifluoroacetic anhydride (0.56 ml) areadded successively to a solution cooled down to 0° C. of tert-butyl2-[(6-amino-3-nitropyridin-2-yl)amino]ethyl carbamate (840 mg, 1 eq) indichloromethane (25 ml). After stirring for 1 hour at 0° C., water (10ml) is added to the mixture. After decantation and extractions, thecombined organic phases are washed with salt water, dried over Na₂SO₄then concentrated under reduced pressure at 40° C. The yellow solidobtained is recrystallized from a dichloromethane/heptane mixture andwashed with diethyl ether (910 mg; 81% yield).

NMR (¹H, 400 MHz, DMSO-d₆): δ 1.31 (s, 9H), 3.22 (dd, 2H), 3.62 (dd,2H), 6.86 (t, 1H), 7.27 (d, 1H), 8.50 (d, 1H), 11.90 (s, 1H).

Stage 3: tert-butyl2-({3-amino-6-[(trifluoroacetyl)amino]pyridin-2-yl}amino)ethyl carbamate

Tert-butyl2-({3-nitro-6-[(trifluoroacetyl)amino]pyridin-2-yl}amino)ethyl carbamate(900 mg) in solution in a mixture of ethyl acetate/ethanol 2:1 (120 ml),and 10% palladium on carbon (130 mg) are introduced into an autoclave.After stirring for 15 hours under a hydrogen atmosphere (3 bar) at atemperature of approximately 20° C., the catalyst is eliminated byfiltration on celite and the filtrate is concentrated under reducedpressure at 40° C. in order to produce the expected compound (820 mg;98% yield).

MS/LC: calculated MM=363.3; m/z=364.2 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 1.36 (s, 9H), 3.15 (dd, 2H), 3.37 (dd, 2H), 4.70 (m, 2H), 5.77 (t,1H), 6.72 (d, 1H), 6.79 (t,1H), 6.88 (d, 1H), 10.81 (s, 1H).

Stage 4: tert-butyl2-{5-[(trifluoroacetyl)amino]-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate

3,4,5-trimethoxyphenyl isothiocyanate (600 mg, 1.2 eq) andN-cyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; load 1.9 mmol/g; 4.6 g, 4 eq) are added successively to asolution of tert-butyl2-({3-amino-6-[(trifluoroacetyl)amino]pyridin-2-yl}amino)ethyl carbamate(800 mg, 1 eq) in tetrahydrofuran (50 ml). The mixture is heated toreflux for 24 hours then cooled down to ambient temperature and filteredon frit. The filtrate is concentrated under reduced pressure at 40° C.Purification of the residue by flash chromatography on silica gel(eluent: heptane/ethyl acetate 6:4 to 3:7) produces the expectedcompound in the form of a cream solid (750 mg; 62% yield).

MS/LC: calculated MM=554.5; m/z=555.2 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 1.24 (s, 9H), 3.32 (m, 2H), 3.63 (s, 3H), 3.79 (s, 6H), 4.30 (m, 2H),6.95 (t, 1H), 7.31 (s, 2H), 7.59 (d, 1H), 7.72 (d, 1H), 8.93 (s, 1H),11.7 (s, 1H).

Stage 5: tert-butyl2-{5-amino-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate

Potassium carbonate (1.17 g, 10 eq) is added to tert-butyl2-{5-[(trifluoroacetyl)amino]-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate (470 mg, 1 eq) in methanol (32 ml) and water (2 ml). Themixture is heated to reflux for 26 hours then cooled down to ambienttemperature and concentrated under reduced pressure at 40° C. Water (15ml) and dichloromethane (50 ml) are added to the residue. Afterdecantation and extractions, the combined organic phases are washed withsalt water, dried over Na₂SO₄ then concentrated under reduced pressureat 40° C. in order to produce the expected compound (379 mg; 97% yield).

MS/LC: calculated MM=458.5; m/z=459.2 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 1.31 (s, 9H), 3.25 (m, 2H), 3.61 (s, 3H), 3.77 (s, 6H), 4.13 (t, 2H),5.50 (m, 2H), 6.22 (d, 1H), 7.01 (t, 1H), 7.21 (s, 2H), 7.37 (d, 1H),8.50 (s, 1H).

Stage 6: tert-butyl2-{5-[(2-propylpentanoyl)amino]-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate

Morpholino-methylpolystyrene (acquired from Novabiochem; load 3.64mmol/g; 33 mg, 1.5 eq) and 2-propylpentanoyl chloride (15 mg, 1.2 eq)are added successively to a solution of tert-butyl2-{5-amino-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate (37 mg, 1 eq) in dichloromethane (2 ml). The mixture isstirred for 1 hour at a temperature of approximately 20° C. thenfiltered on frit. The filtrate is concentrated under reduced pressure at40° C. Purification of the residue by flash chromatography on silica gel(eluent: heptane/ethyl acetate 4:6 to 3:7) produces the expectedcompound (34 mg; 73% yield).

MS/LC: calculated MM=584.7; m/z=585.3 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.86 (t, 6H), 1.27 (s, 9H), 1.18-1.34 (m, 6H), 1.53 (m, 2H), 2.65 (m,1H), 3.31 (m, 2H), 3.63 (s, 3H), 3.79 (s, 6H), 4.25 (t, 2H), 7.0 (t,1H), 7.30 (s, 2H), 7.61 (d, 1H), 7.92 (d, 1H), 8.80 (s, 1H), 10.18 (s,1H).

Stage 7:N-{3-(2-aminoethyl)-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-5-yl}-2-propylpentanamidehydrochloride

A solution of hydrochloric acid in dioxane (4N, 1 ml) is added to asolution of tert-butyl2-{5-[(2-propylpentanoyl)amino]-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate (30 mg) in ethyl acetate (1 ml). After stirring for 1 hour ata temperature of approximately 20° C., the mixture is concentrated underreduced pressure at 40° C. The solid obtained is washed with ethyl etherand dried (29 mg, 97% yield).

MS/LC: calculated MM=485.2; m/z=484.6 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.86 (t, 6H), 1.18-1.36 (m, 6H), 1.56 (m, 2H), 2.62 (m, 1H), 3.31 (m,2H), 3.69 (s, 3H), 3.79 (s, 6H), 4.66 (t, 2H), 7.0 (m, 2H), 7.72 (d,1H), 8.03 (d, 1H), 8.49 (m, 3H), 10.58 (s, 1H).

EXAMPLE D2N-{3-(2-aminoethyl)-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-5-yl}-N′-(sec-butyl)thiourea

Stage 1: tert-butyl2-{5-{[(sec-butylamino)carbonothioyl]amino}-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate

A solution of tert-butyl2-{5-amino-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate prepared according to Example D1 (37 mg, 1 eq) and sec-butylisothiocyanate (20 mg, 2 eq) in tetrahydrofuran (3 ml) is heated toreflux for 17 hours then cooled down to ambient temperature andconcentrated under reduced pressure at 40° C. Purification of theresidue by flash chromatography on silica gel (eluent: heptane/ethylacetate 4:6 to 3:7) produces the expected compound (30 mg; 65% yield).

MS/LC: calculated MM=573.7; m/z=574.2 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.94 (t, 3H), 1.23 (s, 9H), 1.29 (d, 3H), 1.68 (m, 1H), 1.75 (m, 1H),3.31 (m, 2H), 3.62 (s, 3H), 3.78 (s, 6H), 4.25 (t, 2H), 4.30 (m, 1H),6.90 (d, 1H), 6.95 (t, 1H), 7.27 (s, 2H), 7.67 (d, 1H), 8.82 (s, 1H),10.37 (s, 1H), 11.04 (d, 1H).

Stage 2:N-{3-(2-aminoethyl)-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-5-yl}-N′-(sec-butyl)thioureahydrochloride

A solution of hydrochloric acid in dioxane (4N, 0.7 ml) is added to asolution of tert-butyl2-{5-{[(sec-butylamino)carbonothioyl]amino}2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethylcarbamate (22 mg) in ethyl acetate (1 ml). After stirring for 1 hour ata temperature of approximately 20° C., the mixture is concentrated underreduced pressure at 40° C. The solid obtained is washed with ethyl etherand dried (20 mg, 91% yield).

MS/LC: calculated MM=473.6; m/z=474.2 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.94 (t, 3H), 1.27 (d, 3H), 1.69 (m, 2H), 3.31 (m, 2H), 3.67 (s, 3H),3.79 (s, 6H), 4.32 (m, 1H), 4.68 (m, 2H), 7.10 (d, 1H), 7.18 (m, 2H),7.78 (d, 1H), 8.53 (s, 3H), 10.50 (m, 1H), 10.60 (s, 1H).

According to reaction diagram D and according to the procedure describedforN-{3-(2-aminoethyl)-2-[(3,4,5-trimethoxyphenyl)amino]-3H-imidazo[4,5-b]pyridin-5-yl}-2-propylpentanamidehydrochloride, the following compounds can be prepared:

-   in which R₁R₂N represents one of the radicals below:

-   R₃ represents one of the radicals below:

-   and R₄ represents one of the radicals below:

E. Preparation According to Reaction Diagram E:

As described in diagram E, the chlorinated derivative (1) preparedaccording to reaction diagram A, can react with a primary amine, in thepresence of an organic base such as a tertiary amine or an inorganicbase such as potassium or caesium carbonate, in a polar aprotic solventsuch as acetonitrile, dimethylformamide or HMPA at a temperature of20-70° C. for 2-18 hours in order to produce compound (18). The nitrofunction of compound (18) is reduced by catalytic hydrogenation in thepresence of 10% palladium on carbon in an inert solvent such asmethanol, ethanol, ethyl acetate or a mixture of these solvents, at atemperature of 18-25° C., for 2 to 8 hours in order to produce thedianiline (19). Derivative (19) is then treated with an isothiocyanatein the presence of a coupling agent supported or not supported on aresin such as diisopropylcarbodiimide or dicyclohexylcarbodiimide orN-cyclohexylcarbodiimide N-methyl polystyrene resin in an inert solventsuch as tetrahydrofuran, methylene chloride, or chloroform at atemperature of 20-70° C. for 2 to 72 hours in order to producederivative (20). Alternatively, derivative (19) can be treated with anisothiocyanate in an inert solvent such as tetrahydrofuran, methylenechloride, chloroform or ethanol at a temperature of 20-80° C. for 1-16hours then the resultant thiourea can be treated with yellow mercury(II)oxide in the presence of a catalytic quantity of sulphur in a polarsolvent such as methanol or ethanol for 2 to 24 hours at a temperatureof 20-80° C. in order to produce (20). Derivative (20) can react with anacid chloride in an aprotic solvent such as dichloromethane ortetrahydrofuran in the presence of a base such as a tertiary aminesupported or not supported on a resin, such as triethylamine ormorpholino-methylpolystyrene resin at a temperature of 0-40° C. for0.3-2 hours in order to produce the amide (21). The aniline (20) canalso react with an isothiocyanate in an aprotic solvent such astetrahydrofuran at a temperature of 20-70° C. for 548 hours in order toproduce the thiourea (22).

EXAMPLE E1N-[2-[(4-acetylphenyl)amino]-3-(3-piperidin-1-ylpropyl)-3H-imidazo[4,5-b]pyridin-5-yl]-N-butylbutanamidehydrochloride

Stage 1:N⁶-butyl-3-nitro-N²-(3-piperidin-1-ylpropyl)pyridine-2,6-diamine

Potassium carbonate (930 mg, 2 eq) and a solution of 1-butylamine (300mg, 1.2 eq) in acetonitrile (2 ml) are added successively to a solutionof 6-chloro-3-nitro-N-(3-piperidin-1-ylpropyl)pyridin-2-amine (1 g, 1eq; prepared according to Example A2) in acetonitrile (80 ml). Themixture is heated to reflux for 15 hours then cooled down to ambienttemperature and concentrated under reduced pressure at 40° C. Theresidue is taken up in dichloromethane (200 ml) and water (90 ml). Afterdecantation and extractions, the combined organic phases are washed withsalt water, dried over Na₂SO₄ then concentrated under reduced pressureat 40° C. Purification of the residue obtained, by flash chromatographyon silica gel (eluent: heptane/ethyl acetate 9:1 to 100% ethyl acetate),produces the expected compound (1.1 g; 98% yield).

MS/LC: calculated MM=335.4; m/z=336.4 (MH+) NMR (¹H, 400 MHz, DMSO-d₆):δ 0.89 (t, 3H), 1.34 (m, 4H), 1.48 (m, 6H), 1.72 (m, 2H), 2.29 (m, 6H),3.33 (m, 2H), 3.53 (m, 2H), 5.90 (d, 1H), 7.91 (d, 1H), 8.06 (t, 1H),9.12 (t, 1H).

Stage 2:1-(4-{[5-(butylamino)-3-(3-piperidin-1-ylpropyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino}phenyl)ethanone

N⁶-butyl-3-nitro-N²-(3-piperidin-1-ylpropyl)pyridine-2,6-diamine (500mg) in solution in a mixture of ethyl acetate/ethanol 3:1 (10 ml), and10% palladium on carbon (50 mg) are introduced into an autoclave. Afterstirring for 3 hours under a hydrogen atmosphere (3 bar) at atemperature of approximately 20° C., the mixture is filtered on celitein a flask containing a solution of 4-acetylphenyl-isothiocyanate (270mg, 1 eq) in tetrahydrofuran (10 ml).N-cyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; load 1.9 mmol/g; 2.63 g, 3 eq) is added to the filtratethus obtained. The mixture is heated to reflux for 15 hours, cooled downto ambient temperature then filtered on frit and the filtrate isconcentrated under reduced pressure at 40° C. Purification of theresidue by flash chromatography on silica gel (eluent: 100%dichloromethane to dichloromethane/methanol 9:1) produces the expectedcompound (230 mg; 34% yield).

MS/LC: calculated MM=448.6; m/z=449.3 (MH+)

Stage 3:N-[2-[(4-acetylphenyl)amino]-3-(3-piperidin-1-ylpropyl)-3H-imidazo[4,5-b]pyridin-5-yl]-N-butylbutanamidehydrochloride

Morpholinomethyl resin (acquired from Novabiochem, load=3.5 mmol/g; 69mg, 2 eq) and butyryl chloride (17 mg) are added successively to asolution of1-(4-{[5-(butylamino)-3-(3-piperidin-1-ylpropyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino}phenyl)ethanone(54 mg) in anhydrous dichloromethane (1 ml). After stirring for 30minutes at ambient temperature, aminomethylpolystyrene resin is added inorder to trap the excess of acid chloride. After stirring for 2 hours atambient temperature, the mixture is filtered and concentrated underreduced pressure at 40° C. The corresponding hydrochloride salt isformed by adding a 1N solution of hydrochloric acid in ethyl ether. Theprecipitate obtained is filtered and dried in order to produce theexpected compound (68 mg).

MS/LC: calculated MM=518.7; m/z=519.4 (MH+).

According to reaction diagram E and according to the procedure describedforN-[2-[(4-acetylphenyl)amino]-3-(3-piperidin-1-ylpropyl)-3H-imidazo[4,5-b]pyridin-5-yl]-N-butylbutanamidehydrochloride, the following compounds can be prepared:

-   in which R₁R₂N represents one of the radicals below:

-   R₃ represents one of the radicals below:

-   and R₄ represents one of the radicals below:

A subject of the present invention is also a process for the preparationof a compound of formula (I) as defined above, characterized in that thecompound of general formula:

-   in which R₁, R₂, R₄ have the meaning indicated above, is treated    with an isothiocyanate of general formula R₃N═C═S in which R₃ has    the meaning above, in the presence of a coupling agent or yellow    mercury(II) oxide in the presence of sulphur, for a duration of 3 to    48 hours, in a protic or aprotic solvent, at a temperature of 50 to    80° C.

The coupling agent can be supported such asN-methylcyclohexylcarbodiimide N-methyl polystyrene resin or notsupported such as diisopropylcarbodiimide, diethylcarbodiimide ordicyclohexylcarbodiimide. A protic solvent such as methanol or ethanolor an aprotic solvent such as tetrahydrofuran or acetonitrile can beused.

A subject of the invention is also a compound of general formula (II)

in racemic, or enantiomeric form or any combinations of these forms andin which:

-   R₁ and R₂ represent, independently, the hydrogen atom, a    (C₁-C₈)alkyl radical optionally substituted by hydroxy;    (C₂-C₆)alkenylalkenyl, a bicycloalkyl or a radical of formula    —(CH₂)_(n)—X₁ or —X—(CH₂)_(n′)—X′₁;-   X represents —C(O)— or —C(S)—NH—;-   X₁ represents a (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl, adamantyl,    heterocycloalkyl, aryl or heteroaryl radical,    -   the (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl and heteroaryl        radicals being optionally substituted by one or more identical        or different substituents chosen from: —(CH₂)_(n1)—V₁—Y₁, halo,        nitro and cyano;    -   V₁ represents —O—, —S— or a covalent bond;    -   Y₁ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo radicals, or aryl;    -   n and n′ represent an integer from 0 to 6 and n, an integer from        0 to 2 (it being understood that when n is equal to 0, then X₁        does not represent the alkoxy radical);-   X′₁ represents the hydrogen atom; a (C₁-C₆)alkyl radical optionally    substituted by one or more identical or different halo radicals;    (C₃-C₇)cycloalkyl; or aryl optionally substituted by one or more    identical or different substituents chosen from: halo, nitro, cyano,    (C₁-C₆)alkyl optionally substituted by one or more identical or    different halo radicals, and (C₁-C₆)alkoxy optionally substituted by    one or more identical or different halo radicals;-   or R₁ and R₂ form together, with the nitrogen atom to which they are    attached, a heterobicycloalkyl or a heterocycloalkyl optionally    substituted by one or more identical or different substituents    chosen from: hydroxy, (C₁-C₆)alkyl, (C₁-C₆)hydroxyalkyl,    (C₁-C₆)alkoxy-carbonyl, —(CH₂)_(n″)-A, —C(O)—NV₁′Y₁′, and    heterocycloalkyl; or R₁ and R₂ form together a radical of formula:

-   V₁′ and Y₁′ represent, independently, the hydrogen atom or a    (C₁-C₆)alkyl radical;-   A represents an aryl radical optionally substituted by one or more    identical or different substituents chosen from: halo, nitro, cyano,    (C₁-C₆)alkyl optionally substituted by one or more identical or    different halo radicals, and (C₁-C₆)alkoxy optionally substituted by    one or more identical or different halo radicals;-   n″ represents an integer from 0 to 2;-   R₃ represents —(CH₂)_(p)-Z₃ or —C(O)-Z′₃    -   Z₃ represents a (C₁-C₆)alkyl, (C₂-C₆)alkenylalkenyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-carbonyl,        (C₁-C₆)alkyl-amino-carbonyl, (C₃-C₇)cycloalkyl,        heterocycloalkyl, aryl or heteroaryl radical,    -   the (C₃-C₇)cycloalkyl and heterocycloalkyl radicals being        optionally substituted by one or more identical or different        (C₁-C₆)alkyl radicals,    -   the aryl radical being optionally substituted by one or more        identical or different substituents chosen from: halo, nitro,        azido or —(CH₂)_(p′)—V₃—Y₃;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —NH—C(O)—,        —C(O)—NR′₃—, —NH—C(O)—NR′₃—, —NH—C(O)—NR′₃—O— (to illustrate a        preference which is not exemplified) or a covalent bond;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   or Z₃ represents a radical of formula

-   -   Z′₃ represents an aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo,        nitro and —(CH₂)_(p″)—V′₃—Y′₃;    -   V′₃ represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR′₃—, —NH—C(O)—,        —NH—C(O)—NR′₃— or a covalent bond;    -   Y′₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   R′₃ represents the hydrogen atom, a (C₁-C₆)alkyl or        (C₁-C₆)alkoxy radical;    -   p, p′ and p″ represent, independently, an integer from 0 to 4;

-   R₄ represents a radical of formula —(CH₂)_(s)—R′₄;

-   R′₄ represents a heterocycloalkyl containing at least one nitrogen    atom and optionally substituted by (C₁-C₆)alkyl or aralkyl; a    heteroaryl containing at least one nitrogen atom and optionally    substituted by (C₁-C₆)alkyl; or a radical of formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl, (C₂-C₆)alkenyl        alkenyl; (C₃-C₇)cycloalkyl optionally substituted by one or more        identical or different (C₁-C₆)alkyl substituents; cyclohexene;        heteroaryl, aryl optionally substituted by one or more identical        or different radicals chosen from: —(CH₂)_(s″)—V₄—Y₄, halo and        nitro;        -   V₄ represents —O—, —S—, —NH—C(O)—, —NV₄′- or a covalent            bond;        -   Y₄ represents a hydrogen atom or a (C₁-C₆)alkyl radical            optionally substituted by one or more identical or different            halo radicals;        -   V₄′ represents a hydrogen atom or a (C₁-C₆)alkyl;        -   s″ represents an integer from 0 to 4;    -   or Z₄ represents a radical of formula

-   -   s and s′ represent, independently, an integer from 0 to 6;        or a pharmaceutically acceptable salt thereof.

Preferably, the invention relates to compounds of formula II as definedabove and in which

-   R₁ and R₂ represent, independently, the hydrogen atom, a    (C₁-C₈)alkyl radical, a bicycloalkyl or a radical of formula    —(CH₂)_(n)—X₁ or —X—(CH₂)_(n′)—X′₁;-   X represents —C(O)— or —C(S)—NH—;-   X₁ represents a (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl or heteroaryl    radical;-   X′₁ represents the hydrogen atom, a (C₁-C₆)alkyl radical optionally    substituted by one or more identical or different halo radicals,    (C₃-C₇)cycloalkyl or aryl radical;-   or R₁ and R₂ form together, with the nitrogen atom to which they are    attached, a heterobicycloalkyl or a heterocycloalkyl optionally    substituted by one or more identical or different substituents    chosen from: (C₁-C₆)alkyl, (C₁-C₆)alkoxy-carbonyl and —(CH₂)_(n″)-A;-   A represents an aryl radical optionally substituted by one or more    identical or different substituents chosen from: halo and    (C₁-C₆)alkyl;-   n″ represents an integer from 0 to 3;-   R₃ represents —(CH₂)_(p)-Z₃ or —C(O)-Z′₃    -   Z₃ aryl optionally substituted by one or more identical or        different substituents chosen from: halo, nitro and        —(CH₂)_(p′)—V₃—Y₃;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —NH—C(O)—, —C(O)—NR′₃—        or a covalent bond;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   or Z₃ represents a radical of formula

-   -   Z′₃ represents an aryl radical optionally substituted by one or        more identical or different substituents chosen from: halo and        —(CH₂)_(p″)—V′₃—Y′₃;    -   V′₃ represents —O— or a covalent bond;    -   Y′₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical;    -   R′₃ represents the hydrogen atom;    -   p, p′ and p″ represent, independently, an integer from 0 to 4;

-   R₄ represents a radical of formula —(CH₂)_(s)—R′₄

-   R′₄ represents a heterocycloalkyl containing at least one nitrogen    atom; or a radical of formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)allyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl or aryl optionally        substituted by one or more identical or different radicals        chosen from: —(CH₂)_(s″)—V₄—Y₄;        -   V₄ represents —O—;        -   Y₄ represents a (C₁-C₆)alkyl radical optionally substituted            by one or more identical or different halo radicals;        -   s″ represents an integer from 0 to 4;    -   s and s′ represent, independently, an integer from 0 to 6; or a        pharmaceutically acceptable salt thereof,        and more particularly

-   the cycloalkyl radical is chosen from cyclopropyl and cyclohexyl;    and/or

-   the bicycloalkyl radical is bicyclo[2,2,1]heptane, and/or

-   the heteroaryl radical is the furyl radical, and/or

-   the aryl radical is the phenyl radical, and/or

-   the heterobicycloalkyl is 7-aza-bicyclo[2,2,1]heptane, and/or

-   the heterocycloalkyl is chosen from piperidine and piperazine.

Very preferentially also, the invention relates to compounds of formulaII as defined above and in which

-   R₁ and R₂ represent, independently, the hydrogen atom, a    (C₁-C₈)alkyl radical or a radical of formula —(CH₂)_(n)—X₁;-   X₁ represents a (C₃-C₇)cycloalkyl radical and more particularly    cyclopropyl or cyclohexyl;-   or R₁ and R₂ form together, with the nitrogen atom to which they are    attached, a heterocycloalkyl optionally substituted by one or more    identical or different (C₁-C₆)alkyl substituents; and/or-   R₃ represents —(CH₂)_(p)-Z₃    -   Z₃ represents a (C₁-C₆)alkoxy-carbonyl,        (C₁-C₆)alkyl-amino-carbonyl, or phenyl radical optionally        substituted by one or more identical or different substituents        chosen from: nitro and —(CH₂)_(p′)—V₃—Y₃;    -   V₃ represents —O—, —C(O)—, —C(O)—O—, —NH—C(O)—, —C(O)—NR′₃—,— or        —NH—C(O)—NR′₃— or —NH—C(O)—NR′₃—O—;    -   Y₃ represents the hydrogen atom or a (C₁-C₆)alkyl radical        optionally substituted by one or more identical or different        halo radicals;    -   R′₃ represents the hydrogen atom;    -   p and p′ represent, independently, an integer from 0 to 4;        and/or-   R₄ represents a radical of formula —(CH₂)_(s)—R′₄-   R′₄ represents a heterocycloalkyl containing at least one nitrogen    atom and optionally substituted by (C₁-C₆)alkyl; or a radical of    formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Z₄;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl,        (C₃-C₇)cycloalkyl;    -   s and s′ represent, independently, an integer from 0 to 6;        and more particularly the cycloalkyl is chosen from cyclopropyl        and cyclohexyl, and/or the heterocycloalkyl is chosen from:        pyrrolidine, piperidine, morpholine, piperazine; or a        pharmaceutically acceptable salt thereof.

Compounds I and II of the present invention possess usefulpharmacological properties. This is how it was discovered that compoundsI of the present invention possess a good affinity for certain sub-typesof melanocortin receptors, in particular MC4 receptors.

The compounds of the present invention can thus be used in differenttherapeutic applications. They can advantageously be used in order totreat the pathological states or diseases in which one or moremelanocortin receptors are involved such as inflammatory states, weightdisorders (obesity, cachexia, anorexia), sexual activity disorders(erective disorders), pain, but also mental disorders (anxiety,depression), drug addiction, skin diseases (acne, dermatoses,melanomas). Hereafter, in the experimental part, there is anillustration of the pharmacological properties of the compounds of theinvention.

A subject of the present Application is also pharmaceutical compositionscontaining, as active ingredient, at least one product of formula I asdefined above, as well as the pharmaceutically acceptable salts of saidproduct of formula I, in combination with a pharmaceutically acceptablesupport.

By pharmaceutically acceptable salt, is meant in particular additionsalts of inorganic acids such as hydrochloride, hydrobromide,hydroiodide, sulphate, phosphate, diphosphate and nitrate or organicacids such as acetate, maleate, fumarate, tartrate, succinate, citrate,lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate.Also included in the field of the present invention, when they can beused, are the salts formed from bases such as sodium or potassiumhydroxide. For other examples of pharmaceutically acceptable salts,reference can be made to “Salt selection for basic drugs”, Int. J.Pharm. (1986), 33, 201-217.

A subject of the present Application is also the use of the compoundsaccording to the present invention, for the preparation of a medicamentfor the treatment of weight disorders such as obesity, cachexia and moreparticularly cancer cachexia, AIDS cachexia, old age cachexia, cardiaccachexia, renal cachexia, rheumatoid arthritis cachexia, and anorexia,the treatment of pain and more particularly neuropathic pain, thetreatment of mental disorders such as anxiety and depression, thetreatment of sexual activity disorders such as erective disorders.

The pharmaceutical composition can be in the form of a solid, forexample, powders, granules, tablets, gelatin capsules or suppositories.Appropriate solid supports can be, for example, calcium phosphate,magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in liquid form, for example, solutions, emulsions,suspensions or syrups. Appropriate liquid supports can be, for example,water, organic solvents such as glycerol or the glycols, as well astheir mixtures, in varying proportions, in water, added to oils orpharmaceutically acceptable fats. The sterile liquid compositions can beused for intramuscular, intraperitoneal or sub-cutaneous injections andthe sterile compositions can also be administered by intravenousinjection.

All the technical and scientific terms used in the present text have themeaning known to a person skilled in the art. Moreover, all the patents(or patent applications) as well as the other bibliographical referencesare incorporated by way of reference.

Experimental Part:

The compounds according to the invention obtained according to theprocedures of Examples A, B, C, D and E previously described, are shownin the table below.

The compounds are characterized by their retention time (rt) and theirmolecular peak determined by mass spectrometry (MH+).

For the mass spectrometry, a single quadripole mass spectrometer(Micromass, Platform model) equipped with an electrospray source is usedwith a resolution of 0.8 Da at 50% valley. Calibration is carried outmonthly between the masses 80 and 1000 Da using a calibrating mixture ofsodium iodide and rubidium iodide in solution in an isopropanol/watermixture (1/1 Vol.)

For the liquid chromatography, a Waters system including an in-linedegasser, a Waters 600 quaternary pump, a Gilson 233 plate samplinginjector and a Waters PAD 996 UV detector, are used.

The elution conditions used are the following:

-   Eluent A water+0.04% trifluoroacetic acid B acetonitrile

T (min) A % B % 1 95 5 8.5 5 95 10.5 5 95 10.6 95 5 14.9 95 5 15.0 95 5

-   Flow rate: 1 ml/min-   Injection: 10 μl-   Column: Uptisphere ODS 3 μm 75*4.6 mm i.d.

These examples are presented in order to illustrate the above proceduresand should in no event be considered as a limit to the scope of theinvention.

rt Examples Molecular structures [M + H]+ (min) 1

441.2 7.5 2

471.3 8.0 3

439.2 7.3 4

443.2 7.8 5

499.2 7.5 6

532.3 8.2 7

552.2 7.2 8

417.1 7.0 9

471.3 8.0 10

499.3 8.4 11

619.4 8.9 12

455.1 7.5 13

485.2 7.8 14

457.2 7.5 15

469.2 7.6 16

457.3 7.5 17

497.3 8.0 18

483.3 7.8 19

485.3 7.8 20

505.2 7.8 21

455.2 7.5 22

469.2 7.6 23

474.2 7.6 24

513.3 8.5 25

483.3 8.6 26

467.3 8.4 27

453.3 8.5 28

423.3 8.5 29

483.3 8.6 30

491.2 9.4 31

469.3 8.7 32

517.3 8.7 33

453.3 8.5 34

501.2 8.8 35

485.2 10.2 36

465.3 10.5 37

453.2 8.5 38

471.3 7.3 39

513.3 7.8 40

467.3 7.2 41

429.2 7.0 42

441.2 7.0 43

485.3 7.5 44

469.3 7.3 45

453.2 7.0 46

451.3 8.0 47

405.2 7.4 48

367.2 7.2 49

485.2 7.5 50

425.3 8.2 51

395.3 8.0 52

531.2 9.6 53

455.3 8.2 54

463.2 8.8 55

455.3 8.2 56

441.3 8.2 57

453.3 8.1 58

425.3 8.1 59

423.3 8.3 60

473.2 8.3 61

457.2 9.4 62

437.2 9.8 63

453.3 9.6 64

423.2 9.6 65

513.3 9.6 66

489.2 8.4 67

429.2 8.2 68

437.3 8.1 69

441.2 8.2 70

437.2 8.4 71

473.1 8.3 72

451.2 8.5 73

479.2 8.4 74

423.3 8.3 75

437.2 8.0 76

453.2 8.2 77

397.1 7.8 78

442.1 7.9 79

409.0 7.8 80

413.0 7.9 81

411.0 7.8 82

461.0 7.9 83

429.0 8.7 84

457.1 7.8 85

427.1 7.7 86

440.0 8.7 87

397.1 7.8 88

425.1 8.2 89

453.1 8.5 90

409.2 7.8 91

409.2 7.8 92

409.0 7.8 93

437.0 8.1 94

465.2 8.5 95

421.0 7.8 96

421.2 7.8 97

457.1 7.8 98

469.1 7.8 99

507.3 9.1 100

523.3 9.3 101

537.3 9.5 102

437.2 8.4 103

451.3 8.6 104

453.3 8.6 105

467.3 8.8 106

452.3 8.0 107

425.2 7.9 108

453.3 8.2 109

481.3 8.7 110

437.2 7.9 111

481.3 8.6 112

411.2 7.7 113

437.2 8.0 114

423.2 8.3 115

479.3 9.0 116

435.2 8.3 117

479.3 8.9 118

409.2 8.1 119

435.2 8.3 120

477.2 8.1 121

505.2 8.5 122

533.3 9.0 123

489.2 8.1 124

505.3 8.4 125

533.3 8.9 126

489.2 8.2 127

424.3 7.6 128

452.3 7.9 129

480.4 8.3 130

436.3 7.6 131

452.3 7.9 132

480.4 8.2 133

410.3 7.4 134

436.3 7.6 135

423.1 7.8 136

451.1 8.2 137

435.1 7.8 138

451.2 8.1 139

395.0 7.9 140

423.0 8.3 141

407.0 7.9 142

423.0 8.3 143

423.2 7.9 144

451.2 8.3 145

435.2 7.9 146

451.3 8.2 147

479.2 8.0 148

507.3 8.4 149

491.3 8.0 150

507.3 8.4 151

423.3 7.3 152

439.3 7.2 153

438.3 7.2 154

423.2 7.4 155

439.3 7.5 156

438.3 7.2 157

492.4 7.3 158

520.4 7.6 159

504.4 7.3 160

520.4 7.6 161

437.3 8.3 162

453.3 8.4 163

452.3 8.0 164

465.3 8.0 165

493.4 8.5 166

477.3 8.1 167

493.4 8.4 168

479.4 8.2 169

505.4 8.4 170

421.3 7.4 171

449.4 7.6 172

435.3 7.5 173

449.4 7.7 174

477.4 8.0 175

491.4 8.3 176

449.4 7.6 177

626.4 8.8 178

535.4 8.4 179

519.4 8.8 180

505.3 8.6 181

445.4 8.4 182

533.3 8.9 183

547.4 9.1 184

517.3 8.5 185

531.3 8.7 186

545.3 8.9 187

559.4 9.1 188

493.4 8.7 189

521.4 8.8 190

520.4 8.4 191

506.4 8.4 192

542.3 8.6 193

533.3 8.9 194

533.3 8.9 195

547.3 9.1 196

561.4 9.4 197

559.4 9.2 198

573.4 9.4 199

505.3 8.4 200

519.3 8.7 201

505.3 8.4 202

519.3 8.6 203

512.4 8.6 204

515.4 8.8 205

458.3 8.4 206

472.4 8.5 207

473.4 8.2 208

487.4 8.3 209

393.2 7.2 210

491.6 8.1 211

491.6 8.1Pharmacological Study

The affinity of the compounds of the present invention for the differentsub-types of melanocortin receptors was measured according to proceduresanalogous to those described hereafter for the MC4 receptors.

Studies of the Affinity of the Compounds for the MC4 Receptors ofMelanocortins:

The affinity of the compounds of the invention for the MC4 receptors isdetermined by measuring the inhibition of the binding of [¹²⁵I]-[Nle⁴,D-Phe⁷]-α-MSH to membrane preparations of transfected CHO-K1 cells.

CHO-K1 cells expressing human MC4 receptors in a stable fashion arecultured in an RPMI 1640 medium containing 10% of fetal calf serum, 2 mMof glutamine, 100 U/ml of penicillin, 0.1 mg/ml of streptomycin and 0.5mg/ml of G418. The cells are collected with 0.5 mM of EDTA andcentrifuged at 500 g for 5 minutes at 4° C. The pellet is re-suspendedin a phosphate buffered saline (PBS) medium and centrifuged at 500 g for5 min at 4° C. The pellet is re-suspended in a Tris 50 mM buffer mediumat pH 7.4 and centrifuged at 500 g for 5 minutes at 4° C. The cells arelysed by sonication and centrifuged at 39,000 g for 10 minutes at 4° C.The pellet is re-suspended in Tris 50 mM buffer medium at pH 7.4 andcentrifuged at 50,000 g for 10 minutes at 4° C. The membranes obtainedin this last pellet are stored at −80° C.

Measurement of the competitive inhibition of the binding of[¹²⁵I]-[Nle⁴, D-Phe⁷]-α-MSH to the MC4 receptors is carried out induplicate using polypropylene 96-well plates. The cell membranes (50 μgof proteins/well) are incubated with [¹²⁵I]-[Nle⁴, D-Phe⁷]-α-MSH (0.5nM) for 90 minutes at 37° C. in a 50 mM Tris-HCl buffer medium, pH 7.4,comprising 0.2% of bovine serum albumin (BSA), 5 mM of MgCl₂, and 0.1mg/ml of bacitracin.

The bonded [¹²⁵I]-[Nle⁴, D-Phe⁷]-α-MSH is separated from the free[¹²⁵I]-[Nle⁴, D-Phe⁷]-α-MSH by filtration through GF/C glass fibrefilter plates (Unifilter, Packard) pre-impregnated with 0.1% ofpolyethylenimine (P.E.I.), using a Filtermate 196 (Packard). The filtersare washed with 50 mM Tris-HCl buffer, pH 7.4 at 04° C. and theradioactivity present is determined using a counter (Packard Top Count).

The specific binding is obtained by subtracting the non-specific binding(determined in the presence of 0.1 μM of Nle⁴, D-Phe⁷-α-MSH) of thetotal binding. The data are analyzed by computer-assisted non-linearregression (MDL) and the values of the inhibition constants (Ki) aredetermined.

The agonist or antagonist activity of the MC4 receptors of the compoundsof the present invention were determined by measuring the production ofcyclic AMP by the CHO-K1 cells transfected by the MC4 receptor.

Measurement of the Production of Intracellular Cyclic AMP via the MC4Receptors:

CHO-K1 cells expressing the MC4 receptors of the melanocortins arecultured in 384-well plates in an RPMI 1640 medium with 10% of fœtalcalf serum and 0.5 mg/ml of G418. The cells are washed twice with 50 μlof RPMI medium comprising 0.2% BSA and 0.5 mM of3-isobutyl-1-methylxanthine (IBMX).

In order to measure the agonist effect of a compound, the cells areincubated for 5 minutes at 37° C. in the presence of 0.5 mM of IBMX,then stimulation of the production of cyclic AMP is obtained by addingthe compound at concentrations comprised between 1 pM and 10 μM induplicate for 20 minutes at 37° C. The antagonist effect of a compoundis measured by the simultaneous addition of Nle⁴, D-Phe⁷-α-MSH atconcentrations comprised between 1 pM and 10 μM, in the presence of thecompound to be tested, at concentrations comprised between 0.1 nM and 10μM in duplicate for 20 minutes at 37° C.

The reaction medium is eliminated and 80 μl of lysis buffer is added.The intracellular cyclic AMP level is measured by a competition testwith fluorescent cyclic AMP (CatchPoint, Molecular Devices).

1. A compound of the formula

in racemic, or enantiomeric form or any combinations of these forms andwherein: R₁ and R₂ are, independently, selected from the groupconsisting of hydrogen, (C₁-C₈)alkyl optionally substituted by hydroxy,(C₂-C₆)alkenyl; bicycloalkyl, —(CH₂)_(n)—X₁ and —X—(CH₂)_(n′)—X′₁; X isselected from the group consisting of —C(O)— or —C(S)—NH—; X₁ isselected from the group consisting of (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl,adamantyl, heterocycloalkyl, aryl and heteroaryl, The (C₃-C₇)cycloalkyl,heterocycloalkyl, aryl and heteroaryl being optionally substituted by atleast one member selected from the group consisting of:—(CH₂)_(n1)—V₁—Y₁, halo, nitro and cyano; V₁ is selected from the groupconsisting of —O—, —S— or covalent bond; Y₁ is (C₁-C₆)alkyl optionallysubstituted by at least one halo, or aryl; n and n′ are integers from 0to 6 and n₁ an integer from 0 to 2 (it being understood that when n isequal to 0, then X₁ is not alkoxy); X′₁ is selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl optionally substituted by at leastone halo, (C₃-C₇)cycloalkyl; and aryl optionally substituted by at leastone member: halo, nitro, cyano, (C₁-C₆)alkyl-carbonyl, (C₁-C₆)alkyloptionally substituted by at least one halo, and (C₁-C₆)alkoxyoptionally substituted by at least one halo; or R₁ and R₂ form together,with the nitrogen atom to which they are attached, a heterobicycloalkylor a heterocycloalkyl optionally substituted by at least one memberselected from the group consisting of: hydroxy, (C₁-C₆)alkyl optionallysubstituted by hydroxy, (C₁-C₆)alkyl-carbonyl, —(CH₂)_(n″)-A,—C(O)—NV₁′—Y₁′, and heterocycloalkyl; or R₁ and R₂ form together amember selected from the group consisting of:

V₁′ and Y₁′ are, independently, hydrogen or (C₁-C₆)alkyl; A is aryloptionally substituted by at least one member selected from the groupconsisting of: halo, nitro, cyano, (C₁-C₆)alkyl optionally substitutedby at least one member selected from the group halo, and (C₁-C₆)alkoxyoptionally substituted by at least one halo; n″ is an integer from 0 to2; R₃ is selected from the group consisting of -Z₃,—C(R_(z3))(R′_(z3))-Z₃—C(R_(z3))(R′_(z3))—(CH₂)_(p)-Z₃ and —C(O)-Z′₃;R_(z3) and R′_(z3) are, independently, hydrogen or (C₁-C₆)alkyl; Z₃ isselected from the group consisting of Z_(3a), Z_(3b), Z_(3c), Z_(3d),and Z_(3e); Z_(3a) is (C₁-C₆)alkyl or (C₂-C₆)alkenyl; Z_(3b) is selectedfrom the group consisting of (C₁-C₆)alkoxy, C₁-C₆)alkylthio,C₁-C₆)alkylamino and di((C₁-C₆)alkyl)amino; Z_(3c) is aryl orheteroaryl; the aryl and heteroaryl being optionally substituted by atleast one member selected from the group consisting of: halo, cyano,nitro, azido, oxy and —(CH₂)_(p′)—V₃—Y₃; V₃ is selected from the groupconsisting of —O—, —S—, —C(O)—, —C(O)—O—, —O(CO)—, —SO₂—, —SO₂NH—,—NR′₃—SO₂—, —NR′₃—, —NR′₃—C(O)—, —C(O)—NR′₃——NH—C(O)—NR′₃— and covalentbond; Y₃ is selected from the group consisting of hydrogen, (C₁-C₆)alkyloptionally substituted by at least one halo; aryl optionally substitutedby at least one member selected from the group consisting of: halo,nitro, (C₁-C₆)alkyl and (C₁-C₆)alkoxy; and aryl-(C₁-C₆)alkyl optionallysubstituted by at least one member selected from the group consistingof: halo, nitro, (C₁-C₆)alkyl and (C₁-C₆)alkoxy; Z_(3d) is selected fromthe group consisting of (C₁-C₆)alkoxy-carbonyl, amino-carbonyl,(C₁-C₆)alkylamino-carbonyl and di((C₁-C₆)alkyl)amino-carbonyl; Z_(3e) isselected from the group consisting of (C₁-C₆)alkyl-C(O)—NH—,(C₃-C₇)cycloalkyl, heteroalkyl, heterocycloalkyl,

the (C₃-C₇)cycloalkyl and heterocycloalkyl being optionally substitutedby at least one oxy or (C₁-C₆)alkyl, Z′₃ is aryl optionally substitutedby at least one member selected from the group consisting of: halo,nitro and —(CH₂)_(p″)—V′₃—Y′₃; V′₃ is selected from the group consistingof —O—, —C(O)—, —C(O)—O—, —O(CO)—NR′₃—, —NR′₃—C(O)—, —NH—C(O)—NR′₃— andcovalent bond; Y′₃ is hydrogen or (C₁-C₆)alkyl optionally substituted byat least one halo; R′₃ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl and (C₁-C₆)alkoxy; p, p′ and p″ are,independently, an integer from 0 to 6; R₄ is —(CH₂)_(s)—R′₄ R′₄ isheterocycloalkyl containing at least one nitrogen atom and optionallysubstituted by (C₁-C₆)alkyl or arakyl; heteroaryl containing at leastone nitrogen atom and optionally substituted by (C₁-C₆)alkyl; and—NW₄W′₄ W₄ is hydrogen or (C₁-C₈)alkyl; W′₄ is —(CH₂)_(s′)-Z₄; Z₄ isselected from the group consisting of hydrogen, (C₁-C₈)alkyl;(C₂-C₆)alkenyl; (C₃-C₇)cycloalkyl optionally substituted by at least one(C₁-C₆)alkyl; cyclohexene; heteroaryl and aryl optionally substituted byat least one member selected from the group consisting of:—(CH₂)_(s″)—V₄—Y₄, halo and nitro; V₄ is selected from the groupconsisting of —O—, —S—, —NH—C(O)—, —NV₄′— and covalent bond; Y₄ ishydrogen or (C₁-C₆)alkyl optionally substituted by at least one halo;V₄′ is hydrogen or (C₁-C₆)alkyl; s″ is an integer from 0 to 4; or Z₄ is

s and s′ are, an integer from 0 to 6; and a pharmaceutically acceptablesalt thereof.
 2. A compound of claim 1, wherein R₁ and R₂ are,independently, selected from the group consisting of hydrogen,(C₁-C₈)alkyl, bicycloalkyl, —(CH₂)_(n)—X₁ and —X—(CH₂)_(n′)—X′₁; X is—C(O)— or —C(S)—NH—; X₁ is selected from the group consisting of(C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl optionally substituted by (C₁-C₆)alkyl,and heteroaryl; X′₁ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally substituted by at least one halo,(C₃-C₇)cycloalkyl or aryl optionally substituted by(C₁-C₆)alkyl-carbonyl; or R₁ and R₂ form together, with the nitrogenatom to which they are attached, are heterobicycloalkyl or aheterocycloalkyl optionally substituted by at least one member selectedfrom the group consisting of: (C₁-C₆)alkyl, (C₁-C₆)alkyl-carbonyl and—(CH₂)_(n″)-A; A is aryl optionally substituted by at least one: halo or(C₁-C₆)alkyl; n″ is an integer from 0 to 1; R₄ is —(CH₂)_(s)—R′₄ R′₄ isheterocycloalkyl containing at least one nitrogen atom and optionallysubstituted by (C₁-C₆)alkyl; or —NW₄W′₄ W₄ is hydrogen, (C₁-C₈)alkyl;W′₄ is —(CH₂)_(s′)-Z₄; Z₄ is selected from the group consisting ofhydrogen, (C₁-C₈)alkyl and aryl optionally substituted by at least one:—(CH₂)_(s″)—V₄—Y₄; V₄ is —O—; Y₄ is (C₁-C₆)alkyl optionally substitutedby at least one halo; s″ is an integer from 0 to 4; s and s′ are,independently, an integer from 1 to 4; or a pharmaceutically acceptablesalt thereof.
 3. A compound of claim 2, wherein it comprises at leastone of the following characteristics: cycloalkyl chosen fromcyclopropyl, cyclobutyl and cyclohexyl; bicycloalkyl isbicyclo[2,2,1]heptane; heterobicycloalkyl is7-aza-biclyclo[2,2,1]heptane; aryl is phenyl; heteroaryl is furyl;heterocycloalkyl is chosen from piperidine, morpholine and piperazine;or a pharmaceutically acceptable salt thereof.
 4. A compound of claim 1wherein R₁ and R₂ are, independently, hydrogen, (C₁-C₆)alkyl or—(CH₂)_(n)—X₁ or —X—(CH₂)_(n′)—X′₁; X is —C(O)—; X₁ is(C₃-C₇)cycloalkyl; X′₁ is hydrogen or (C₁-C₆)cycloalkyl; n is 0 or 1; n′is an integer from 0 to 5; or R₁ and R₂ form together, with the nitrogenatom to which they are attached, are heterocycloalkyl optionallysubstituted by at least one (C₁-C₆)alkyl; or a pharmaceuticallyacceptable salt thereof.
 5. A compound of claim 4, wherein the(C₃-C₇)cycloalkyl of X₁ and X′₁ is chosen from cyclopropyl, cyclobutyland cyclohexyl; and heterocycloalkyl that together form R₁ and R₂, ispiperidine; or a pharmaceutically acceptable salt thereof.
 6. A compoundof claim 1 wherein R₄ is —(CH₂)_(s)—R′₄ R′₄ is heterocycloalkylcontaining at least one nitrogen atom and optionally substituted by(C₁-C₆)alkyl; or —NW₄W′₄ W₄ is hydrogen or (C₁-C₈)alkyl; W′₄ is—(CH₂)_(s′)-Z₄; Z₄ is hydrogen or (C₁-C₈)alkyl; s and s′ are,independently, an integer from 2 to 4; or a pharmaceutically acceptablesalt thereof.
 7. A compound of claim 6, wherein the heterocycloalkyl ofR′₄ is: piperidine or morpholine; or a pharmaceutically acceptable saltthereof.
 8. A compound of claim 1 wherein R₃ is —C(O)-Z′₃ Z′₃ is aryloptionally substituted by at least one member selected from the groupconsisting of halo and —(CH₂)_(p″)—V′₃—Y′₃; V′₃ is —O— or covalent bond;Y′₃ is hydrogen or (C₁-C₆)alkyl optionally substituted by at least onehalo; p″ is an integer from 0 to 2; or a pharmaceutically acceptablesalt thereof.
 9. A compound of claim 1 wherein R₃ is selected from thegroup consisting of Z₃, —C(R_(z3))(R′_(z3))-Z₃ and—C(R_(z3))(R′_(z3))—(CH₂)_(p)-Z₃; or a pharmaceutically acceptable saltthereof.
 10. A compound of claim 9, wherein R₃ is -Z₃ and Z₃ is selectedfrom the group consisting of Z_(3b), Z_(3c), Z_(3e); or apharmaceutically acceptable salt thereof.
 11. A compound of claim 10,wherein Z₃ is Z_(3c) and Z_(3c) is aryl; or a pharmaceuticallyacceptable salt thereof.
 12. A compound of claim 11, wherein Z_(3c) isphenyl substituted by at least one member selected from the groupconsisting of: halo, nitro and —(CH₂)_(p′)—V₃—Y₃; V₃ is selected fromthe group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —SO₂NH—,—NR′₃—C(O)—, —C(O)—NR′₃— and covalent bond; R′₃ is hydrogen; Y₃ ishydrogen or (C₁-C₆)alkyl optionally substituted by at least one halo; ora pharmaceutically acceptable salt thereof.
 13. A compound of claim 11,wherein Z_(3c) is phenyl substituted by at least one —(CH₂)_(p′)—V₃—Y₃;V₃ is selected from the group consisting of —C(O)—, —C(O)—O—, and—C(O)—NR′₃—; R′₃ is hydrogen; Y₃ is hydrogen or (C₁-C₆)alkyl; or apharmaceutically acceptable salt thereof.
 14. A compound of claim 9,wherein R₃ is —C(R_(z3))(R′_(z3))-Z₃ and Z₃ is Z_(3d) or Z_(3e); or apharmaceutically acceptable salt thereof.
 15. A compound of claim 9,wherein R₃ is —C(R_(z3))(R′_(z3))—(CH₂)_(p)-Z₃ and Z₃ is Z_(3c), Z_(3d)or Z_(3e); or a pharmaceutically acceptable salt thereof.
 16. A compoundof claim 15, wherein Z₃ is Z_(3d) or Z_(3e); Z_(3d) is(C₁-C₆)alkoxy-carbonyl or amino-carbonyl; Z_(3e) is selected from thegroup consisting of (C₁-C₆)alkyl-C(O)—NH—, heterocycloalkyl optionallysubstituted by oxy, or

or pharmaceutically acceptable salt thereof.
 17. A process for thepreparation of a compound of claim 1 comprising reacting a compound ofthe formula:

wherein R₁, R₂, R₄ have the meaning of claim 1, with an isothiocyanateof the formula R₃N═C═S in which R₃ has the meaning indicated in claim 1,in the presence of a coupling agent or of yellow mercury(II) oxide inthe presence of sulfur, for a duration of 3 to 48 hours, in a protic oraprotic solvent, at a temperature of 50 to 80° C.
 18. A pharmaceuticalcomposition for treating weight disorders comprising an effective amountof a compound of claim 1 sufficient to treat said disorder and an inertpharmaceutical carrier.
 19. A method of treating a condition selectedfrom the group consisting of obesity, anxiety, depression, pain anderectile dysfunction in warm-blooded animals comprising administering towarm-blooded animals in need thereof an amount of a compound of claim 1sufficient to treat said condition.
 20. The method of claim 19 whereinthe condition being treated is anxiety and depression.
 21. The method ofclaim 19 wherein the condition being treated is pain.
 22. The method ofclaim 21 wherein the pain is neuropathic pain.